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Journal articles on the topic 'CDK2 inhibitors'

Author: Grafiati

Published: 5 June 2025

Last updated: 15 July 2025

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1

Fang, Douglas D., Yueqin Liu, Yang Liu, Wei Sha, and Charles Z. Ding. "Abstract 3021: Discovery of a novel and selective CDK2 inhibitor for targeted cancer therapy." Cancer Research 85, no. 8_Supplement_1 (2025): 3021. https://doi.org/10.1158/1538-7445.am2025-3021.

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Targeted inhibition of CDK2 presents a promising therapeutic strategy for breast cancer patients who experience disease progression following CDK4/6-based therapies. In addition, CDK2 hyperactivity or CCNE1 amplification drives the progression of many cancer types, making it an attractive target. However, developing CDK inhibitors is often complicated by toxicities resulting from off-target inhibition of other CDK family members, particularly CDK1 and CDK9, which are essential for normal cell proliferation and survival. Achieving selectivity for CDK2 is therefore crucial to maximize therapeuti

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2

Mou, Jiajia, Danghui Chen, and Yanru Deng. "Inhibitors of Cyclin-Dependent Kinase 1/2 for Anticancer Treatment." Medicinal Chemistry 16, no. 3 (2020): 307–25. http://dx.doi.org/10.2174/1573406415666190626113900.

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Background: The cell cycle is regulated by cyclin-dependent kinases (CDKs) and their cognate cyclins, along with their endogenous inhibitors (CDKIs). CDKs act as central regulators in this process. Different CDKs play relevant roles in different phases. Among all CDKs, CDK1 is indispensible, which can drive all events that are required in the cell cycle in the absence of interphase CDKs (CDK2, CDK3, CDK4 and CDK6). So, CDK1 is an attractive target for anticancer drug development. Methods: CDK1 and CDK2 have 89.19% similar residues and 74.32% identical residues, their structures especially the

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3

Denz, Christopher R., Michael Grondine, Jun Fan, et al. "Abstract ND06: First disclosure of AZD8421, a highly selective CDK2 inhibitor to address resistance to CDK4/6 inhibitors in breast and CCNE1-high cancers." Cancer Research 84, no. 7_Supplement (2024): ND06. http://dx.doi.org/10.1158/1538-7445.am2024-nd06.

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Abstract Cyclin-dependent kinases (CDKs) are an attractive class of cancer targets due to their role in cell-cycle regulation. CDK2 is a Ser/Thr kinase activated via interaction with its cyclin partners CCNE and CCNA, driving G1/S progression of the cell cycle. CDK2 inhibition has the potential to address multiple resistance mechanisms to CDK4/6 inhibitors in breast cancer. In addition, CCNE1 is frequently amplified and over-expressed in cancers including ovarian, with pre-clinical data linking CDK2 inhibition sensitivity to high CCNE1. First-generation inhibitors targeting CDK2 suffered from

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4

Niu, Chengshan, Meihua Li, Shaoqing Chen, et al. "Abstract 5338: TY-1781, a potent and highly selective CDK2 inhibitor, demonstrates superior anti-tumor activity in CCNE1 high-expression solid tumor models." Cancer Research 85, no. 8_Supplement_1 (2025): 5338. https://doi.org/10.1158/1538-7445.am2025-5338.

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Abstract Background: The common prescription of Palbociclib and other approved CDK4/6 inhibitors in clinic have greatly benefitted breast cancer patients worldwide. The cell cycle regulation therapy however has been found that the long-term use of the CDK4/6 inhibition agents eventually causes primary or acquired resistance to the therapy, and patients eventually relapse from the treatment. Approximately 20% of patients treated with CDK4/6 inhibitors show initial treatment failure. Based on the finding that abnormal activation of CDK2/Cyclin E1 due to CCNE1 gene amplification is determined the

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5

Bai, Chang, Nansong Xia, Yexing Cao, et al. "Abstract LB223: Discovery of INV-6452, a CDK2/4 inhibitor for the treatment of HR-positive HER2-negative breast cancer resistant to current CDK4/6 therapy." Cancer Research 85, no. 8_Supplement_2 (2025): LB223. https://doi.org/10.1158/1538-7445.am2025-lb223.

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Abstract CDK4/6 Inhibitors represented by palbociclib, ribociclib, abemaciclib and dalpiciclib, working through their inhibitory activities toward G1/S transition cyclin-dependent protein kinases 4 and 6 coupled with cyclins D1 and D3, have emerged as one of the mainstream therapies for HR positive HER2 negative breast cancer. However, some patients do not respond to CDK4/6 inhibitors well, and more importantly majority of patients eventually develop resistance to CDK4/6 inhibitors. Such resistance is often attributed to alterations in downstream signaling cascade, including activation of CDK2

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6

Canduri, F., N. J. F. da Silveira, J. C. Camera Jr, and W. F. de Azevedo Jr. "Structural bioinformatics study of cyclin-dependent kinases complexed with inhibitors." Eclética Química 28, no. 1 (2003): 45–53. http://dx.doi.org/10.1590/s0100-46702003000100006.

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The present work describes molecular models for the binary complexes CDK9, CDK5 and CDK1 complexed with Flavopiridol and Roscovitine. These structural models indicate that the inhibitors strongly bind to the ATP-binding pocket of CDKs and the structural comparison with the complexes CDK2:Flavopiridol and CDK2:Roscovitine correlates the structural differences with differences in inhibition of these CDKs by the inhibitors. These structures open the possibility of testing new inhibitor families, in addition to new substituents for the already known lead structures such as flavones and adenine der

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7

Salman Roghani, Roham, Ali Sanjari moghaddam, Gabrielle Rupprecht, et al. "A precision medicine drug discovery pipeline to identify dual CDK2/9 inhibition as a novel treatment for colorectal cancer." Journal of Clinical Oncology 38, no. 15_suppl (2020): e16056-e16056. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16056.

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e16056 Background: Colorectal cancer (CRC) is the 3rdmost common form of cancer in the US, responsible for over 50,000 death each year. Therapeutic options for advanced colorectal cancer are limited, and there remains an unmet clinical need to identify new therapies to treat this deadly disease. To address this need, we have developed a precision medicine pipeline that integrates high throughput chemical screens with matched patient-derived cell lines and patient-derived xenografts (PDXs) to identify new treatments for CRC. Methods: We used high-throughput chemical screens of 2,100 compounds a

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8

Denz, Christopher R., Michael Grondine, Jun Fan, et al. "Abstract 5730: Targeting the cell cycle with AZD8421, a potent and highly selective CDK2 inhibitor." Cancer Research 84, no. 6_Supplement (2024): 5730. http://dx.doi.org/10.1158/1538-7445.am2024-5730.

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Abstract Cyclin-dependent Kinase 2 (CDK2) is a Ser/Thr kinase activated via interaction with its cyclin partners CCNE and CCNA, driving G1/S progression of the cell cycle. CDK2 inhibition has the potential to address multiple resistance mechanisms to CDK4/6 inhibitors in breast cancer. In addition, CCNE1 is frequently amplified and over-expressed in cancers including ovarian, uterine, breast, gastric and others, with pre-clinical data linking CDK2 inhibition sensitivity to high CCNE1. The CDK2 inhibitor field has historically suffered from high attrition in Phase I due to off-target toxicity.

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9

Chand, Saswati, Michael Hansbury, Yvonne Lo, et al. "Abstract 1143: Development of a CDK2-selective small molecule inhibitor INCB123667 for the treatment of CCNE1hi breast cancers." Cancer Research 83, no. 7_Supplement (2023): 1143. http://dx.doi.org/10.1158/1538-7445.am2023-1143.

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Abstract Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have been approved for treatment of metastatic ER+ HER2− breast cancer as monotherapy or in combination with endocrine therapy. However, many patients become resistant to CDK4/6 therapy due to various mechanisms such as loss of tumor suppressor Rb, hyperactivation of CDK4/6, and/or CDK2/Cyclin E1 expression and activity, resulting in a highly unmet clinical need. Triple-negative breast cancers (TNBC), owing to a lack of hormone receptor (HR) expression and extensive heterogeneity, remain notoriously aggressive and unresponsive to cu

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10

Armand, Jessica, Sungsoo Kim, Kibum Kim, Eugene Son, Minah Kim, and Hee Won Yang. "Abstract 430: Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer." Cancer Research 85, no. 8_Supplement_1 (2025): 430. https://doi.org/10.1158/1538-7445.am2025-430.

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Abstract The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy has revolutionized treatment for hormone receptor-positive (HR+) metastatic breast cancer. However, the emergence of resistance in most patients often leads to treatment discontinuation with no consensus on effective second-line therapies. The therapeutic benefits of maintaining CDK4/6i or incorporating CDK2 inhibitors (CDK2i) after disease progression remain unclear. Here, we demonstrate that sustained CDK4/6i therapy, either alone or combined with CDK2i, significantly suppresses the growth of drug-resistant HR+ bre

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11

Nunoda, Kousuke, Tetsuzo Tauchi, Tomoiku Takaku, et al. "Identification and Functional Significance of Genes Regulated by Structurally Different ABL Kinase Inhibitors." Blood 106, no. 11 (2005): 2860. http://dx.doi.org/10.1182/blood.v106.11.2860.2860.

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Abstract Imatinib is an ABL-specific inhibitor that binds with high affinity to the inactive conformation of the BCR-ABL tyrosine kinase and has been shown to be effective in the treatment of chronic myelogenous leukemia. Dasatinib is an ATP-competitive, dual-spesific SRC and ABL kinase inhibitor that can bind BCR-ABL in both the active and inactive conformations. From a clinical stand point, dasatinib is particular attractive because it has been shown to induce hematologic and cytogenetic responses in imatinib-resistant CML patients. In the view of the fact that the combination of imatinib an

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12

Arora, Mansi, Justin Moser, Timothy E. Hoffman, et al. "Abstract 5992: Cells rapidly adapt to CDK2 inhibitors via plasticity of the CDK2/4/6-Rb-E2F axis." Cancer Research 83, no. 7_Supplement (2023): 5992. http://dx.doi.org/10.1158/1538-7445.am2023-5992.

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Abstract CDK2 is a core cell-cycle enzyme that phosphorylates a variety of substrates to drive progression through the cell cycle. CDK2 is hyperactivated in multiple cancers and is therefore an attractive therapeutic target. Here, application of a novel small molecule CDK2/4/6 inhibitor, PF-06873600, enabled in-depth interrogation of CDK2 substrate phosphorylation, cell-cycle progression, and drug adaptation in preclinical models. CDK2-specific inhibition leads to rapid loss of substrate phosphorylation, but unexpectedly, CDK2 substrate phosphorylation rebounds within several hours. Whereas CD

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13

Shen, Chen, Ming Qiu, Nanni Huser, et al. "Abstract 5709: PF-07104091, a first-in-class CDK2-selective inhibitor for the treatment of HR+/HER2- breast cancer and CCNE1high ovarian cancer." Cancer Research 84, no. 6_Supplement (2024): 5709. http://dx.doi.org/10.1158/1538-7445.am2024-5709.

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Abstract The selective inhibition of Cyclin\CDK complexes controlling cell cycle progression has been established as cancer therapy by selective CDK4/6 inhibitors in HR+/HER2- breast cancer. Expanding control of the cell cycle through selective inhibition of CDK2 offers novel therapeutic opportunities in cancer, including targeting CCNE1 amplified tumors and countering resistance to CDK4\6 inhibitors in ER+ breast cancer. PF-07104091 is a first-in-class CDK2-selective inhibitor under clinical investigation in patients with HR+/HER2- breast cancer and ovarian cancer. Preclinical studies using P

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14

Li, Meihua, Chengshan Niu, Mingtao Chen, et al. "Abstract 5979: TY-0540, a highly potent CDK2/4/6 inhibitor, attenuates acquired resistance against CDK4/6 inhibition." Cancer Research 83, no. 7_Supplement (2023): 5979. http://dx.doi.org/10.1158/1538-7445.am2023-5979.

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Abstract The introduction of cyclin-dependent kinase (CDK) 4 and 6 dual inhibitors significantly improves the progression-free survival of patients with ER+/HER2- advanced or metastatic breast cancer. A large cohort of patients, however, eventually relapse to CDK4/6 therapy. To further empower the CDK therapy, simultaneous targeting of CDK2, CDK4, and CDK6 has been proposed as a new strategy based on the finding that abnormal activation of CDK2/CyclinE1 due to CCNE1 gene amplification is determined the key resistant mechanism to CDK4/6 inhibition. Here we present preclinical data of TY-0540, a

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15

Ilic-Widlund, Nina, William Tahaney, Vasia Vafeiadou, et al. "Abstract P5-01-26: Selective Targeting of CDK2 Using Molecular Glue Degraders for the Treatment of HR-Positive/HER2-Negative Breast Cancer." Clinical Cancer Research 31, no. 12_Supplement (2025): P5–01–26—P5–01–26. https://doi.org/10.1158/1557-3265.sabcs24-p5-01-26.

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Abstract Cyclin dependent kinases 4 and 6 (CDK4 and CDK6) and cyclin dependent kinase 2 (CDK2) act sequentially to coordinate cell cycle progression through the G1/S phases and effectively drive cell proliferation via RB phosphorylation and repression. CDK4/6 inhibitors in combination with endocrine therapy are approved agents for the treatment of hormone-receptor (HR)-positive/HER2-negative breast cancer. While these agents offer substantial benefit, patients eventually relapse. It has been reported that approximately 30% of resistant tumors following CDK4/6 inhibitor treatment exhibit upregu

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16

Pal-Ghosh, Ruma, Danfeng Xue, Rod Warburton, Nicholas Hill, Peter Polgar, and Jamie L. Wilson. "CDC2 Is an Important Driver of Vascular Smooth Muscle Cell Proliferation via FOXM1 and PLK1 in Pulmonary Arterial Hypertension." International Journal of Molecular Sciences 22, no. 13 (2021): 6943. http://dx.doi.org/10.3390/ijms22136943.

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A key feature of pulmonary arterial hypertension (PAH) is the hyperplastic proliferation exhibited by the vascular smooth muscle cells from patients (HPASMC). The growth inducers FOXM1 and PLK1 are highly upregulated in these cells. The mechanism by which these two proteins direct aberrant growth in these cells is not clear. Herein, we identify cyclin-dependent kinase 1 (CDK1), also termed cell division cycle protein 2 (CDC2), as having a primary role in promoting progress of the cell cycle leading to proliferation in HPASMC. HPASMC obtained from PAH patients and pulmonary arteries from Sugen/

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17

Fanta, Biruk Sintayehu, Jimma Lenjisa, Theodosia Teo, et al. "Discovery of N,4-Di(1H-pyrazol-4-yl)pyrimidin-2-amine-Derived CDK2 Inhibitors as Potential Anticancer Agents: Design, Synthesis, and Evaluation." Molecules 28, no. 7 (2023): 2951. http://dx.doi.org/10.3390/molecules28072951.

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Cyclin-dependent kinase 2 (CDK2) has been garnering considerable interest as a target to develop new cancer treatments and to ameliorate resistance to CDK4/6 inhibitors. However, a selective CDK2 inhibitor has yet to be clinically approved. With the desire to discover novel, potent, and selective CDK2 inhibitors, the phenylsulfonamide moiety of our previous lead compound 1 was bioisosterically replaced with pyrazole derivatives, affording a novel series of N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amines that exhibited potent CDK2 inhibitory activity. Among them, 15 was the most potent CDK2 inhibitor

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18

Gkountela, Sofia, William Tahaney, Vasiliki Vafeiadou, et al. "Abstract LB422: Selective targeting of CDK2 using molecular glue degraders for the treatment of HR-positive/HER2-negative breast cancer." Cancer Research 85, no. 8_Supplement_2 (2025): LB422. https://doi.org/10.1158/1538-7445.am2025-lb422.

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Abstract Cyclin dependent kinases 4 and 6 (CDK4 and CDK6) and cyclin dependent kinase 2 (CDK2) act in a coordinated fashion to phosphorylate and repress RB protein, effectively driving cell proliferation via E2F activation. Currently, CDK4/6 inhibitors in combination with endocrine therapy are considered the standard of care for the treatment of hormone-receptor (HR)-positive/HER2-negative breast cancer, but unfortunately most patients with metastatic disease ultimately progress. High CCNE1 expression is considered one of the underlying mechanisms of resistance to CDK4/6-inhibition, and other

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19

Latham, K. M., S. W. Eastman, A. Wong, and P. W. Hinds. "Inhibition of p53-mediated growth arrest by overexpression of cyclin-dependent kinases." Molecular and Cellular Biology 16, no. 8 (1996): 4445–55. http://dx.doi.org/10.1128/mcb.16.8.4445.

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Rat fibroblasts transformed by a temperature-sensitive mutant of murine p53 undergo a reversible growth arrest in G1 at 32.5 degrees C, the temperature at which p53 adopts a wild-type conformation. The arrested cells contain inactive cyclin-dependent kinase 2 (cdk2) despite the presence of high levels of cyclin E and cdk-activating kinase activity. This is due in part to p53-dependent expression of the p2l cdk inhibitor. Upon shift to 39 degrees C, wild-type p53 is lost and cdk2 activation and pRb phosphorylation occur concomitantly with loss of p2l. This p53-mediated growth arrest can be abro

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20

Harper, J. W., S. J. Elledge, K. Keyomarsi, et al. "Inhibition of cyclin-dependent kinases by p21." Molecular Biology of the Cell 6, no. 4 (1995): 387–400. http://dx.doi.org/10.1091/mbc.6.4.387.

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p21Cip1 is a cyclin-dependent kinase (Cdk) inhibitor that is transcriptionally activated by p53 in response to DNA damage. We have explored the interaction of p21 with the currently known Cdks. p21 effectively inhibits Cdk2, Cdk3, Cdk4, and Cdk6 kinases (Ki 0.5-15 nM) but is much less effective toward Cdc2/cyclin B (Ki approximately 400 nM) and Cdk5/p35 (Ki > 2 microM), and does not associate with Cdk7/cyclin H. Overexpression of P21 arrests cells in G1. Thus, p21 is not a universal inhibitor of Cdks but displays selectivity for G1/S Cdk/cyclin complexes. Association of p21 with Cdks is gre

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Hsieh, Fen F., Lou Ann Barnett, Wayne F. Green, et al. "Cell cycle exit during terminal erythroid differentiation is associated with accumulation of p27Kip1 and inactivation of cdk2 kinase." Blood 96, no. 8 (2000): 2746–54. http://dx.doi.org/10.1182/blood.v96.8.2746.h8002746_2746_2754.

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Progression through the mammalian cell cycle is regulated by cyclins, cyclin- dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs). The function of these proteins in the irreversible growth arrest associated with terminally differentiated cells is largely unknown. The function of Cip/Kip proteins p21Cip1and p27Kip1 during erythropoietin-induced terminal differentiation of primary erythroblasts isolated from the spleens of mice infected with the anemia-inducing strain of Friend virus was investigated. Both p21Cip1 and p27Kip1 proteins were induced during erythroid differentia

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Chan, F. K., J. Zhang, L. Cheng, D. N. Shapiro, and A. Winoto. "Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4." Molecular and Cellular Biology 15, no. 5 (1995): 2682–88. http://dx.doi.org/10.1128/mcb.15.5.2682.

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The cell cycle in mammalian cells is regulated by a series of cyclins and cyclin-dependent kinases (CDKs). The G1/S checkpoint is mainly dictated by the kinase activities of the cyclin D-CDK4 and/or cyclin D-CDK6 complex and the cyclin E-CDK2 complex. These G1 kinases can in turn be regulated by cell cycle inhibitors, which may cause the cells to arrest at the G1 phase. In T-cell hybridomas, addition of anti-T-cell receptor antibody results not only in G1 arrest but also in apoptosis. In searching for a protein(s) which might interact with Nur77, an orphan steroid receptor required for activat

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Kim, Jae-Min, Ah-Rong Nam, Kyoung-Seok Oh, et al. "Abstract 5711: Anti-tumor effects of fadraciclib, CDK2/9 inhibitor, in biliary tract cancer." Cancer Research 84, no. 6_Supplement (2024): 5711. http://dx.doi.org/10.1158/1538-7445.am2024-5711.

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Abstract Background: Targeting CDKs has emerged as a significant strategy in the development of new drugs. The CDK4/6 inhibitors have proven their efficacy in several tumor types, while the CDK2 and CDK9 inhibitors are currently undergoing clinical trials. In biliary tract cancer (BTC), gene expressions of CDK2 and CDK9 are elevated compared to normal tissue. CDK9, a transcriptional CDK, regulates RNA polymerase II (RNAP II), leading to enhanced transcription of oncogenes, such as MCL1. Aberrant activation of these CDKs is associated with cancer progression and evading apoptosis in BTC. Notabl

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Hsieh, Fen F., Lou Ann Barnett, Wayne F. Green, et al. "Cell cycle exit during terminal erythroid differentiation is associated with accumulation of p27Kip1 and inactivation of cdk2 kinase." Blood 96, no. 8 (2000): 2746–54. http://dx.doi.org/10.1182/blood.v96.8.2746.

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Abstract Progression through the mammalian cell cycle is regulated by cyclins, cyclin- dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs). The function of these proteins in the irreversible growth arrest associated with terminally differentiated cells is largely unknown. The function of Cip/Kip proteins p21Cip1and p27Kip1 during erythropoietin-induced terminal differentiation of primary erythroblasts isolated from the spleens of mice infected with the anemia-inducing strain of Friend virus was investigated. Both p21Cip1 and p27Kip1 proteins were induced during erythroid di

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Fassl, Anne, Christopher Brain, Monther Abu-Remaileh, et al. "Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition." Science Advances 6, no. 25 (2020): eabb2210. http://dx.doi.org/10.1126/sciadv.abb2210.

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Inhibitors of cyclin-dependent kinases CDK4 and CDK6 have been approved for treatment of hormone receptor–positive breast cancers. In contrast, triple-negative breast cancers (TNBCs) are resistant to CDK4/6 inhibition. Here, we demonstrate that a subset of TNBC critically requires CDK4/6 for proliferation, and yet, these TNBC are resistant to CDK4/6 inhibition due to sequestration of CDK4/6 inhibitors into tumor cell lysosomes. This sequestration is caused by enhanced lysosomal biogenesis and increased lysosomal numbers in TNBC cells. We developed new CDK4/6 inhibitor compounds that evade the

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McConnell, Beth B., Fiona J. Gregory, Francesca J. Stott, Eiji Hara, and Gordon Peters. "Induced Expression of p16INK4a Inhibits Both CDK4- and CDK2-Associated Kinase Activity by Reassortment of Cyclin-CDK-Inhibitor Complexes." Molecular and Cellular Biology 19, no. 3 (1999): 1981–89. http://dx.doi.org/10.1128/mcb.19.3.1981.

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ABSTRACT To investigate the mode of action of the p16 INK4a tumor suppressor protein, we have established U2-OS cells in which the expression of p16 INK4a can be regulated by addition or removal of isopropyl-β-d-thiogalactopyranoside. As expected, induction of p16 INK4a results in a G1 cell cycle arrest by inhibiting phosphorylation of the retinoblastoma protein (pRb) by the cyclin-dependent kinases CDK4 and CDK6. However, induction of p16 INK4a also causes marked inhibition of CDK2 activity. In the case of cyclin E-CDK2, this is brought about by reassortment of cyclin, CDK, and CDK-inhibitor

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Swarbrick, Alexander, Christine S. L. Lee, Robert L. Sutherland, and Elizabeth A. Musgrove. "Cooperation of p27Kip1 and p18INK4c in Progestin-Mediated Cell Cycle Arrest in T-47D Breast Cancer Cells." Molecular and Cellular Biology 20, no. 7 (2000): 2581–91. http://dx.doi.org/10.1128/mcb.20.7.2581-2591.2000.

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ABSTRACT The steroid hormone progesterone regulates proliferation and differentiation in the mammary gland and uterus by cell cycle phase-specific actions. The long-term effect of progestins on T-47D breast cancer cells is inhibition of cellular proliferation. This is accompanied by decreased G1 cyclin-dependent kinase (CDK) activities, redistribution of the CDK inhibitor p27Kip1among these CDK complexes, and alterations in the elution profile of cyclin E-Cdk2 upon gel filtration chromatography, such that high-molecular-weight complexes predominate. This study aimed to determine the relative c

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Watts, Lotte P., Lisa Nguyen, Marissa Baker, et al. "Abstract 5335: A comparative study of CDK2 inhibitors." Cancer Research 85, no. 8_Supplement_1 (2025): 5335. https://doi.org/10.1158/1538-7445.am2025-5335.

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Abstract CDK2 is a key Cyclin-Dependent Kinase that is responsible for driving cells through the cell cycle. CDK2 is both hyper-activated in a variety of cancers and is a mechanism of resistance to CDK4/6 inhibitors, making it an attractive therapeutic target. Using PF3600 and PF4091 (tagtociclib), we previously showed that upon CDK2 inhibition, cells exhibit a rapid drop in substrate phosphorylation that rebounds within several hours (‘drop-rebound’). We further showed that CDK4/6 activity compensates for inhibition of CDK2 and sustains the proliferative program by maintaining Rb hyper-phosph

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NAKAMURA, K., N. YOKOYAMA, and I. IGARASHI. "Cyclin-dependent kinase inhibitors block erythrocyte invasion and intraerythrocytic development of Babesia bovis in vitro." Parasitology 134, no. 10 (2007): 1347–53. http://dx.doi.org/10.1017/s0031182007002831.

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SUMMARYCyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle. A number of chemicals, which selectively inhibit the CDK activities, have been synthesized for the development of anti-cancer drugs. This report describes the inhibitory effect of purine derivatives known to be CDK inhibitors on the asexual growth of Babesia bovis. The 4 compounds, roscovitine, purvalanol A, CGP74514A, and CDK2 Inhibitor II, showed significantly suppressive effects on the in vitro growth of B. bovis. Three (roscovitine, purvalanol A, and CDK2 Inhibitor II) showed an inhibitory

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Schaefer, Inga-Marie, Meijun Z. Lundberg, Matthew L. Hemming, et al. "Abstract 5648: Response and resistance to CDK2 and CDK4/6 inhibition in GIST." Cancer Research 82, no. 12_Supplement (2022): 5648. http://dx.doi.org/10.1158/1538-7445.am2022-5648.

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Abstract Gastrointestinal stromal tumor (GIST) is the most common GI sarcoma and is generally initiated by KIT or PDGFRA mutations which are compelling therapeutic targets for tyrosine kinase inhibitors (TKI). However, the emergence of secondary mutations results in clinical resistance to available TKIs. GIST progression is driven by genomic events which incrementally target the p16-CDK4/6-RB1 and p14-TP53-RB1 pathways to create CDK4/6 and CDK2 oncogenic co-dependency. Based on limited efficacy of single-agent CDK4/6-inhibitor (CDK4/6i) therapy in GIST, we evaluated strategies of co-targeting

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Susanti, Ni Made Pitri, and Daryono Hadi Tjahjono. "Cyclin-Dependent Kinase 4 and 6 Inhibitors in Cell Cycle Dysregulation for Breast Cancer Treatment." Molecules 26, no. 15 (2021): 4462. http://dx.doi.org/10.3390/molecules26154462.

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In cell development, the cell cycle is crucial, and the cycle progression’s main controllers are endogenous CDK inhibitors, cyclin-dependent kinases (CDKs), and cyclins. In response to the mitogenic signal, cyclin D is produced and retinoblastoma protein (Rb) is phosphorylated due to activated CDK4/CDK6. This causes various proteins required in the cell cycle progression to be generated. In addition, complexes of CDK1-cyclin A/B, CDK2-cyclin E/A, and CDK4/CDK6-cyclin D are required in each phase of this progression. Cell cycle dysregulation has the ability to lead to cancer. Based on its role

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Chen, Grace, Carolina Guido, Natalia Zisman, Krishna Allamneni, and Stacy Wister Blain. "Abstract 6914: p27 small molecule inhibitors for CDK4/6i-resistant metastatic breast cancer (mBC)." Cancer Research 85, no. 8_Supplement_1 (2025): 6914. https://doi.org/10.1158/1538-7445.am2025-6914.

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Abstract Cyclin-dependent kinases 4/6 (CDKs) are key cell cycle regulators that form trimeric complexes with cyclin D1 and the master regulator p27Kip1, acting downstream of proliferation-driving pathways. CDK4/6 inhibitors (CDK4/6i) like palbociclib have been pivotal for the treatment of ER+ mBC but resistance to these drugs is common. This resistance is due to CDK2 activation, which bypasses CDK4/6 inhibition, restoring cell proliferation and suggesting that effective targeting requires simultaneous inhibition of CDK4/6, and CDK2. CDK4/6i work by dissolving the trimeric CDK4/6-cyclin D1 comp

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Chen, Yaoyu, Jinhong Chen, Yali Guo, et al. "Abstract B173: The anti-tumor activity of CDK2 inhibition alone or in combination with other anti-cancer agents in human cancers." Molecular Cancer Therapeutics 22, no. 12_Supplement (2023): B173. http://dx.doi.org/10.1158/1535-7163.targ-23-b173.

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Abstract Cyclin-dependent kinase 2 (CDK2) plays a crucial role in the regulation of the cell cycle and is involved in a variety of biological processes. It is responsible for phosphorylating proteins involved in G1 and S phase cell cycle progression, DNA damage response, intracellular transport, protein degradation, signal transduction, and DNA and RNA metabolism. CDK2 activity is particularly significant in cells exhibiting CCNE1 amplification or overexpression. Additionally, CDK2 activity has been linked to potential resistance against chemotherapy or targeted therapy. Several studies have i

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Hirai, H., M. F. Roussel, J. Y. Kato, R. A. Ashmun, and C. J. Sherr. "Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6." Molecular and Cellular Biology 15, no. 5 (1995): 2672–81. http://dx.doi.org/10.1128/mcb.15.5.2672.

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Cyclin D-dependent kinases act as mitogen-responsive, rate-limiting controllers of G1 phase progression in mammalian cells. Two novel members of the mouse INK4 gene family, p19 and p18, that specifically inhibit the kinase activities of CDK4 and CDK6, but do not affect those of cyclin E-CDK2, cyclin A-CDK2, or cyclin B-CDC2, were isolated. Like the previously described human INK4 polypeptides, p16INK4a/MTS1 and p15INK4b/MTS2, mouse p19 and p18 are primarily composed of tandemly repeated ankyrin motifs, each ca. 32 amino acids in length, p19 and p18 bind directly to CDK4 and CDK6, whether untet

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Spencer, Sabrina L. "Abstract SY19-03: Mechanisms of sensitivity and resistance to CDK2 inhibitors." Cancer Research 84, no. 7_Supplement (2024): SY19–03—SY19–03. http://dx.doi.org/10.1158/1538-7445.am2024-sy19-03.

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Abstract CDK2 is a core cell-cycle kinase that phosphorylates many substrates to drive progression through the cell cycle. We used several CDK2 inhibitors in clinical development to interrogate CDK2 substrate phosphorylation, cell-cycle progression, and drug adaptation in preclinical models. In normal mammary cells and estrogen receptor-positive breast cancer cells, CDK2 inhibition causes a rapid loss of substrate phosphorylation that is rapidly restored by a hard-wired cell-cycle buffering mechanism. In this mechanism, CDK4/6 backstops Rb1 hyper-phosphorylation to maintain Cyclin A2 expressio

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Chen, Grace, Natalie Dudas, Kate Coleman, et al. "Abstract LB265: IpY.20: Innovative strategies for post-CDK estrogen receptor (ER)+ metastatic breast cancer (mBC)." Cancer Research 84, no. 7_Supplement (2024): LB265. http://dx.doi.org/10.1158/1538-7445.am2024-lb265.

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Abstract Cyclin-dependent kinases (CDK) 4/6 are key cell cycle regulators that form complexes with cyclin D1 and the master regulator p27Kip1. This ternary complex acts downstream of the ER- and HER2-pathways, which drive cell proliferation. CDK4/6 phosphorylates the Retinoblastoma protein and other substrates, and keeps p27 from inhibiting G1-associated CDK2. Targeted inhibition of CDK4/6 (CDK4/6i) blocks the growth of ER+ and HER2+ BC by dissolving the CDK4/6-cyclin D1 complex and permitting the shuttling of p27 to inhibit CDK2 complex. Approval of CDK 4/6i such as palbociclib, though a game

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Munck, Joanne M., Susan J. Tudhope, Kleopatra Papa, et al. "Abstract 5331: Orthosteric CDK2 kinase inhibitors have a distinctive profile when compared to genetic perturbation of CDK2 in CCNE1-amplified and non-amplified tumor cell lines." Cancer Research 85, no. 8_Supplement_1 (2025): 5331. https://doi.org/10.1158/1538-7445.am2025-5331.

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Abstract Aim: There has been renewed interest in pursuing cyclin-dependent kinase 2 (CDK2) as a therapeutic target for cancer treatment, given its essential role in driving the survival of CCNE1-amplified tumors and mediating resistance to CDK4/6 inhibitor treatment in estrogen receptor positive breast cancer. This has resulted in the identification of a next generation of orthosteric inhibitors which have increased selectivity for CDK2 kinase versus other CDK-family members. This study aimed to contrast genetic and chemical perturbation of CDK2 in human tumor cell lines with and without CCNE1

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Guo, Yali, Jinhong Chen, Nathan Schomer, et al. "Abstract 3026: ARTS-023: a potent and selective CDK4 Inhibitor demonstrating anti-tumor activity in preclinical ER+ breast cancer models." Cancer Research 85, no. 8_Supplement_1 (2025): 3026. https://doi.org/10.1158/1538-7445.am2025-3026.

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Cell cycle deregulation is a hallmark of cancer, and cyclin-dependent kinases (CDKs) play a pivotal role in driving tumor proliferation by regulating cell cycle progression. Among these, CDK4 and CDK6 are critical in promoting cell G1 to S transition. While three CDK4/6 inhibitors have been approved for treating estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancers, eventual relapse and severe hematological toxicities, particularly neutropenia, remain major clinical challenges. Preclinical data suggest that CDK6 dependence is predominantly a

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Sine, Chance, Lotte Watts, Brianna Fernandez, et al. "Abstract 5328: p16 confers sensitivity to CDK2 inhibitors in CCNE1-amplified ovarian cancers." Cancer Research 85, no. 8_Supplement_1 (2025): 5328. https://doi.org/10.1158/1538-7445.am2025-5328.

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Abstract Blocking the cell cycle is a promising avenue for cancer therapy, with Cyclin-Dependent Kinase 2 (CDK2) emerging as a key target. However, in multiple cell types, CDK4/6 activity compensates for CDK2 inhibition and sustains the proliferative program, enabling CDK2 reactivation. Thus, we hypothesized that sensitivity to CDK2 inhibition is linked to the absence of this CDK4/6-mediated compensatory mechanism. Here we show that Cyclin E1-driven ovarian cancers often co-express the tumor suppressor p16, which inhibits CDK4/6. We show that ovarian cancer cells expressing p16 exhibit heighte

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TANRIVERDI, OZGUR, and AYSEGUL YILDIZ. "The Role of Speedy/RINGO Protein in Breast Cancer as a Future Biomarker." Cancer Diagnosis & Prognosis 4, no. 3 (2024): 209–13. http://dx.doi.org/10.21873/cdp.10310.

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Background/Aim: Cyclin-dependent kinases (CDKs) are proteins that require the binding of regulatory subunits called cyclins and play a key role in cell cycle progression and activation. CDKs play a key role in carcinogenesis of many solid malignancies, and inhibition of these proteins has produced anti-cancer effects demonstrated in preclinical studies. This narrative review was conducted to develop a hypothetical approach to determine whether Speedy/RINGO, a protein associated with CDK2, could be a possible predictive factor in breast cancer patients treated with a CDK4/6 inhibitor. Materials

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Lu, Shuyan, Tae Sung, Marina Amaro, Brad Hirakawa, Bart Jessen, and Wenyue Hu. "Phenotypic Characterization of Targeted Knockdown of Cyclin-Dependent Kinases in the Intestinal Epithelial Cells." Toxicological Sciences 177, no. 1 (2020): 226–34. http://dx.doi.org/10.1093/toxsci/kfaa092.

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Abstract Cyclin-dependent kinases (CDKs) are serine/threonine kinases that regulate cell cycle and have been vigorously pursued as druggable targets for cancer. There are over 20 members of the CDK family. Given their structural similarity, selective inhibition by small molecules has been elusive. In addition, collateral damage to highly proliferative normal cells by CDK inhibitors remains a safety concern. Intestinal epithelial cells are highly proliferative and the impact of individual CDK inhibition on intestinal cell proliferation has not been well studied. Using the rat intestinal epithel

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Blain, Stacy Wister, Arianna Chand, Lina Pedraza-Ortiz, et al. "Abstract 1860: NP-ALT, a liposomal:peptide drug, blocks p27Kip1 phosphorylation to cause cell death in CDK4i-resistant breast cancer." Cancer Research 82, no. 12_Supplement (2022): 1860. http://dx.doi.org/10.1158/1538-7445.am2022-1860.

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Abstract Resistance to cyclin D-cdk4/6 inhibitors (CDK4/6i) is frequently caused by compensatory CDK2 activity. We have developed a novel strategy to kill CDK4i resistant tumor cells using a therapeutic liposomal:peptide formulation, NP-ALT, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. IpY is specific for p27, and this reduces toxicity relative to that seen with the small molecule ATP-competitive CDK4/6i or CDK2i. NP-ALT blocks DNA replication in HR+ breast cancer (BC) cells and mouse models, but unlike CDK4/6i or CDK2i treatment, it

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Chen, Pingping, Yinqiu Xu, Xuanyi Li, Hequan Yao, and Kejiang Lin. "Development and strategies of CDK4/6 inhibitors." Future Medicinal Chemistry 12, no. 2 (2020): 127–45. http://dx.doi.org/10.4155/fmc-2019-0062.

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Aim: CDK4/6 have critical roles in the early stage of the cell cycle. CDK2 acts later in the cell cycle and has a considerably broader range of protein substrates, some of which are essential for normal cell proliferation. Therefore, increasing the selectivity of cyclin-dependent kinase (CDK) inhibitors is critical. Methodology: In this study, we construct a versatile, specific CDK4 pharmacophore model that not only matches well with 8119 of the reported 9349 CDK4/6 inhibitors but also differentiates from the CDK2 pharmacophore. Results & Conclusion: we demonstrate the activity and selecti

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Alam, Samina, Brian S. Bowser, Michael J. Conway, et al. "Downregulation of Cdc2/CDK1 Kinase Activity Induces the Synthesis of Noninfectious Human Papillomavirus Type 31b Virions in Organotypic Tissues Exposed to Benzo[a]pyrene." Journal of Virology 84, no. 9 (2010): 4630–45. http://dx.doi.org/10.1128/jvi.02431-09.

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ABSTRACT Epidemiological studies suggest that human papillomavirus (HPV)-infected women who smoke face an increased risk for developing cervical cancer. We have previously reported that exposure of HPV-positive organotypic cultures to benzo[a]pyrene (BaP), a major carcinogen in cigarette smoke, resulted in enhanced viral titers. Since BaP is known to deregulate multiple pathways of cellular proliferation, enhanced virion synthesis could result from carcinogen/host cell interaction. Here, we report that BaP-mediated upregulation of virus synthesis is correlated to an altered balance between cel

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Lashen, Ayat, Mashael Algethami, Shatha Alqahtani, et al. "The Clinicopathological Significance of the Cyclin D1/E1–Cyclin-Dependent Kinase (CDK2/4/6)–Retinoblastoma (RB1/pRB1) Pathway in Epithelial Ovarian Cancers." International Journal of Molecular Sciences 25, no. 7 (2024): 4060. http://dx.doi.org/10.3390/ijms25074060.

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Cyclin-dependent kinases (CDK2, CDK4, CDK6), cyclin D1, cyclin E1 and phosphorylated retinoblastoma (pRB1) are key regulators of the G1/S cell cycle checkpoint and may influence platinum response in ovarian cancers. CDK2/4/6 inhibitors are emerging targets in ovarian cancer therapeutics. In the current study, we evaluated the prognostic and predictive significance of the CDK2/4/6–cyclin D1/E1–pRB1 axis in clinical ovarian cancers (OC). The CDK2/4/6, cyclin D1/E1 and RB1/pRB1 protein expression were investigated in 300 ovarian cancers and correlated with clinicopathological parameters and patie

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Lai, Jiun-I., Yong-Ji Zhuang, Ting-Yi Lin, Ta-Chung Chao, Chun-Yu Liu, and Ling-Ming Tseng. "Abstract P4-01-10: A kinase inhibitor library screen reveals novel candidates that reverse CDK4/6 inhibitor resistance in CDK6 amplified HR(+) breast cancer." Cancer Research 82, no. 4_Supplement (2022): P4–01–10—P4–01–10. http://dx.doi.org/10.1158/1538-7445.sabcs21-p4-01-10.

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Abstract Background and rationale: Metastatic HR (+) breast cancer currently still remains an incurable disease. CDK4/6 inhibitors in combination with endocrine therapy have emerged as standard 1st and 2nd lines in metastatic HR (+) breast cancer. Resistance to CDK4/6 inhibitors eventually occurs, and currently the optimal subsequent treatment for these patients remains unsettled. Based on the excellent tolerability and efficacy of CDK4/6 inhibitors, it remains a clinical interest to identify mechanisms of resistance towards CDK4/6 inhibitors in breast cancer. This is currently an area of inte

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Geng, Jianlin, Ke Liu, Zhiyong Yu, et al. "Abstract 5705: Discovery of a selective slow-off CDK2 inhibitor NKT3447 with distinct features of suppressing pCDK2, downregulating cyclin E, and achieving prolonged pathway inhibition." Cancer Research 84, no. 6_Supplement (2024): 5705. http://dx.doi.org/10.1158/1538-7445.am2024-5705.

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Abstract CDK2 is a cell cycle kinase that plays a critical role in controlling the G1 to S-phase transition and its abnormal activation through cyclin E1(CCNE1) amplification has been indicated as the primary oncogenic driver in advanced cancers including ovarian, endometrial, and gastric cancers. In addition, cyclin E1 overexpression has emerged as a key resistance mechanism to CDK4/6 inhibitors in hormone receptor-positive breast cancer patients. Therefore, CDK2 represents a promising novel oncology target. However, development of a potent and selective CDK2 inhibitor has been challenging du

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Shapiro, Geoffrey I. "Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment." Journal of Clinical Oncology 24, no. 11 (2006): 1770–83. http://dx.doi.org/10.1200/jco.2005.03.7689.

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Cyclin-dependent kinases (cdks) are critical regulators of cell cycle progression and RNA transcription. A variety of genetic and epigenetic events cause universal overactivity of the cell cycle cdks in human cancer, and their inhibition can lead to both cell cycle arrest and apoptosis. However, built-in redundancy may limit the effects of highly selective cdk inhibition. Cdk4/6 inhibition has been shown to induce potent G1 arrest in vitro and tumor regression in vivo; cdk2/1 inhibition has the most potent effects during the S and G2 phases and induces E2F transcription factor–dependent cell d

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Foster, James S., Donald C. Henley, Antonin Bukovsky, Prem Seth, and Jay Wimalasena. "Multifaceted Regulation of Cell Cycle Progression by Estrogen: Regulation of Cdk Inhibitors and Cdc25A Independent of Cyclin D1-Cdk4 Function." Molecular and Cellular Biology 21, no. 3 (2001): 794–810. http://dx.doi.org/10.1128/mcb.21.3.794-810.2001.

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ABSTRACT Estrogens induce proliferation of estrogen receptor (ER)-positive MCF-7 breast cancer cells by stimulating G1/S transition associated with increased cyclin D1 expression, activation of cyclin-dependent kinases (Cdks), and phosphorylation of the retinoblastoma protein (pRb). We have utilized blockade of cyclin D1-Cdk4 complex formation through adenovirus-mediated expression of p16INK4a to demonstrate that estrogen regulates Cdk inhibitor expression and expression of the Cdk-activating phosphatase Cdc25A independent of cyclin D1-Cdk4 function and cell cycle progression. Expression of p1

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Chen, Grace, Lena Stafford, Anusha Aditya, et al. "Abstract 1554: IpY.20, a first-in-class inhibitor of p27Kip1, inhibits CDK4/6 and CDK2 to kill tumor cells." Cancer Research 83, no. 7_Supplement (2023): 1554. http://dx.doi.org/10.1158/1538-7445.am2023-1554.

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Abstract The drug resistance seen in the presence of CDK4/6 inhibitors, such as palbociclib, can be attributed to compensatory activation of tumor cell proliferation by CDK2. While combination therapy of CDK4/6i with Estrogen modulators significantly extends Progression Free Survival (PFS) in patients with metastatic HR+ breast cancer, their tumors invariably develop resistance, which results in only marginal improvement in their Overall Survival (OS). To address this unmet medical need, both CDK4/6 and CDK2 must be inhibited simultaneously. p27Kip1, the natural inhibitor of CDK4/6 and CDK2, i

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