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Journal articles on the topic 'Molecular glue degrader'

Author: Grafiati

Published: 4 June 2025

Last updated: 1 August 2025

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1

Zhang, Yujia, Jessica Bates, Benoit Gourdet, et al. "Abstract 3429: Beyond cereblon IMIDs - biophysics-based discovery of novel molecular glue chemotypes." Cancer Research 83, no. 7_Supplement (2023): 3429. http://dx.doi.org/10.1158/1538-7445.am2023-3429.

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Abstract Molecular glue degraders are compact, low molecular weight molecules that can efficiently induce specific and potent degradation of a target protein. This class of degraders function by inducing interactions between a target of interest and a ubiquitin-ligase, either by stabilization of weak pre-existing interactions, or by generation of entirely novel interactions. These molecules offer significant opportunity beyond heterobifunctional degraders such as PROTACs, not least in terms of improved molecular properties. However, beyond the IMID molecular glues, typified by thalidomide, pom

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Jordan, Allan M., Kuhulika Bhalla, Helen Burston, et al. "Abstract 1660: Seeking new glues - Toward an E3 ligase-agnostic molecular glue degrader identification platform." Cancer Research 85, no. 8_Supplement_1 (2025): 1660. https://doi.org/10.1158/1538-7445.am2025-1660.

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Abstract Targeted Protein Degradation (TPD) is a rapidly growing modality in oncology and is broadly driven by development of bifunctional (PROTAC-type) or monovalent degraders. Whilst the latter group largely consists of molecular glue degraders (MGDs), it also encompasses compounds that act as degraders via allosteric or other mechanisms. Screening for compounds with MGD properties can be undertaken via biophysical methods, where proximity of an effector and target protein is measured, limiting the effect of the compound to a known, selected effector, such as a particular ubiquitin-ligase of

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3

Liu, Yuan, Mads Larsen, Bo Lin, et al. "Abstract 6070: Identification of a molecular glue degrader that engages a cancer-specific E3 ligase." Cancer Research 84, no. 6_Supplement (2024): 6070. http://dx.doi.org/10.1158/1538-7445.am2024-6070.

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Abstract To date, most successful molecular glues have leveraged ubiquitously expressed E3 ligases, most notably Cereblon in the case of the thalidomide derivatives. However, a number of specific E3 ligases are highly over-expressed in certain tumors. Compounds that engage such tumor-specific E3 ligases might provide a unique opportunity to develop molecular glues with higher therapeutic indexes. One such tumor-specific E3 ligase is FBXO5, a member of the F-box family of E3 ligases. Expression analysis suggests this E3 ligase is highly expressed in a wide array of tumor tissues when compared t

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Kang, Incheol, Seungoh Seo, and Seong Hyeok Cho. "Abstract 384: IPS-06061, a novel TPD molecular glue degrader targeting KRAS G12D." Cancer Research 85, no. 8_Supplement_1 (2025): 384. https://doi.org/10.1158/1538-7445.am2025-384.

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Abstract We have discovered a novel KRAS G12D-degrading Molecular Glue using IPS's cutting-edge ProGlu AI-based drug discovery platform and PPIExplorer, an IPS-Chip based Proteomics technology. ProGlu accurately predicts PPI between E3 ligase and KRAS G12D through MD simulation, enabling de novo design of MG degraders. One such degrader, namely IPS-06061, was successfully synthesized and confirmed a strong anti-tumor efficacy using a xenograft animal model. These data demonstrate that KRAS MG will be a promising new therapeutic modality for the treatment of PDA, CRC, and NSCLC. Citation Format

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5

Bouvier, Corentin, Rachel Lawrence, Francesca Cavallo, et al. "Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders." Cells 13, no. 7 (2024): 578. http://dx.doi.org/10.3390/cells13070578.

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Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding to a ubiquitin ligase. More generally referred to as bifunctional degraders, PROTACs have led the way in the field of targeted protein degradation (TPD), with several compounds currently undergoing clinical testing. Alongside bifunctional degraders, single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered as a viable approach for development of therapeutics, driven by advances in rational discovery approaches. This review fo

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Martin, Leenus, Nasrin Rastgoo, Jean-Francois Brazeau, et al. "Abstract 6375: Discovery and characterization of novel, potent and selective CDK2 molecular glue degrader against CCNE1-amplified tumors." Cancer Research 85, no. 8_Supplement_1 (2025): 6375. https://doi.org/10.1158/1538-7445.am2025-6375.

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Abstract Introduction: The Cyclin-Dependent Kinases (CDKs) with their cyclin binding partners are associated with cell cycle progression and transcriptional regulation. Dysregulation of the cell cycle is a hallmark of cancer and targeting CDKs is a key oncology therapeutic strategy. Cyclin E1 (CCNE1) amplification/overexpression and activation of its canonical binding partner CDK2 is a major resistance mechanism in CDK4/6i breast cancer therapy. In addition, elevated CCNE1 expression and complexation with CDK2 promotes aberrant cell cycling which is associated with poor prognosis in ovarian an

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7

Chan, Chi-Chung, Chun-Sing Li, Lihong Hu, Wenxi Li, Zhenzhen Zhu, and Shuhui Chen. "Abstract 393: Discovery of novel, potent and orally active GSPT1 molecular glue degraders." Cancer Research 85, no. 8_Supplement_1 (2025): 393. https://doi.org/10.1158/1538-7445.am2025-393.

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Abstract Molecular glue degrader (MGD) is an emerging therapeutic strategy offering an exciting alternative to traditional small molecules exploring new target space. These small molecules interact with the ubiquitin-proteasome system (UPS) to promote degradation of protein of interest (POI), especially those considered to be challenging targets (e.g., GSPT1, VAV1, WIZ, BCL6, STAT6, IKZFs). In fact, clinical proof of concept has been obtained with immunomodulatory drugs such as thalidomide, lenalidomide and pomalidomide, which degrade IKZF1/IKZF3. GSPT1 (G1 to S phase transition protein 1) is

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8

Duncan, Aundrietta D., Daniela Y. Santiesteban, Nadeem Q. Mirza, et al. "Abstract 6253: SP-3164, a novel molecular glue degrader with activity in preclinical models of multiple myeloma." Cancer Research 83, no. 7_Supplement (2023): 6253. http://dx.doi.org/10.1158/1538-7445.am2023-6253.

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Abstract Multiple myeloma (MM) makes up approximately 10% of all hematologic malignancies, with increasing incidence worldwide. Though treatment options for newly diagnosed patients have evolved in recent years, they are not curative, and relapse is common with 2,500-3,000 relapsed or refractory (R/R) MM US patients seeking novel treatments, annually. Cereblon (CRBN)-binding Ikaros and Aiolos (I/A) protein degraders (i.e., lenalidomide (LEN) and pomalidomide (POM)) have had great success in treating MM. However, due to the unstable chiral nature of the CRBN-binding moiety, common to these mole

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Read, Timothy J., Richard Steel, Leah Damon, et al. "Abstract LB007: Discovery of a novel molecular glue degrader of Nrf2." Cancer Research 85, no. 8_Supplement_2 (2025): LB007. https://doi.org/10.1158/1538-7445.am2025-lb007.

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Abstract Nrf2 is an oncogenic transcription factor that is frequently overactive in tumors bearing mutations in the NRF2/KEAP1 pathway, but to date, no direct Nrf2 inhibitors have been tested clinically. Using high-throughput transcriptomic screens in combination with biophysical assays, we discovered ARP-4922 as a potent molecular glue degrader of Nrf2. ARP-4922 degrades Nrf2 in a proteasome- and cullin- dependent manner with exceptional activity, especially in NRF2/KEAP1-mutant backgrounds. Genetic experiments identified the likely E3 ligase driving ARP-4922-mediated degradation of Nrf2, and

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Au, CheukMan Cherie, Michelle Naidoo, Catrina Estrella, et al. "Abstract 1645: Developing first-in-class AR-V7/AR-fl molecular glue degrader to revolutionize prostate cancer therapeutics." Cancer Research 85, no. 8_Supplement_1 (2025): 1645. https://doi.org/10.1158/1538-7445.am2025-1645.

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Abstract Metastatic castration resistance prostate cancer (mCRPC) is a lethal disease due to the resistance of standard-of-care (SoC) treatments, including androgen receptor (AR) pathway inhibitors and taxanes. Treatment resistance occurs partly due to the expression of constitutively active AR splice variants, that hijack AR signaling even after castration. AR-V7 is the most prevalent variant and is expressed in ∼75% of patients with mCRPC, which confers resistance to SoC treatment. Currently, there is no AR-V7 pharmacologic inhibitor, limiting patients’ therapeutic options. Thus, AR-V7 inhib

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Lin, Chenyu, Zhaoliang Li, Kyle Medley, David J. Bearss, and Hariprasad Vankayalapati. "Abstract LB161: Discovery of an oral, potent, and selective CDK9 molecular glue degrader SLX-3065 active in aggressive variant prostate cancers (AVPC)." Cancer Research 84, no. 7_Supplement (2024): LB161. http://dx.doi.org/10.1158/1538-7445.am2024-lb161.

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Abstract Background: The use of new potent targeted therapies in prostate cancers has led to the resistance and development of highly aggressive variant prostate cancers (AVPC), including neuroendocrine prostate cancers (NEPC). N-MYC and C-MYC oncogenes overexpress in all aggressive prostate cancers (PCa). This overexpression is highly prevalent in these lethal subtypes of cancers, detected in 2% of all Prostate Cancers and over 10-17% of mCRPC patients. Transcriptional targets of CDK9 are MYCs, which act as an oncogenic driver, sufficient to transform human-derived prostate cancer cells to ta

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Cho, Jaeyong, Atsushi Miyagawa, Kazuki Yamaguchi, et al. "UDP-Glucose: A Cereblon-Dependent Glucokinase Protein Degrader." International Journal of Molecular Sciences 23, no. 16 (2022): 9094. http://dx.doi.org/10.3390/ijms23169094.

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We previously reported that glucokinase is ubiquitinated and degraded by cereblon with an unknown endogenous glucokinase protein degrader. Here, we show that UDP-glucose is a glucokinase protein degrader. We identified that both glucose and UDP-glucose bind to glucokinase and that both uridine and UDP-glucose bind to cereblon in a similar way to thalidomide. From these results, UDP-glucose was identified as a molecular glue between cereblon and glucokinase. Glucokinase produces glucose-6-phosphate in the pancreas and liver. Especially in β-cells, glucokinase is the main target of glucose for g

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Fröhlicher, M., A. Del Rio, A. Delise, N. Zamurovic, and V. Dubost. "LP-23 Molecular glue degrader reproductive toxicity: what did we learn?" Toxicology Letters 368 (September 2022): S292. http://dx.doi.org/10.1016/j.toxlet.2022.07.765.

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Jordan, Allan, Philip Addis, Toby Allen, et al. "Abstract LB030: Building a platform of validated high throughput screening approaches for molecular glue degrader identification." Cancer Research 84, no. 7_Supplement (2024): LB030. http://dx.doi.org/10.1158/1538-7445.am2024-lb030.

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Abstract Over recent years, Induced proximity therapeutics (IPT) and targeted protein degradation (TPD) approaches have become increasingly popular. Whilst significant initial efforts focused upon heterobifunctional degraders, molecular glue degraders (MGDs) represent the next generation proximity-based drugs, but their rational discovery remains challenging. Here, we describe unbiased and broadly applicable approaches for molecular glue hit ID through the development of a suite of orthogonal and highly complementary screening approaches, relying on Homogeneous Time-Resolved Fluorescence (HTRF

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Li, Yen-Der, Michelle W. Ma, Muhammad Murtaza Hassan, et al. "Abstract 3424: Template-assisted covalent modification of DCAF16 enables BRD4 molecular glue degraders." Cancer Research 83, no. 7_Supplement (2023): 3424. http://dx.doi.org/10.1158/1538-7445.am2023-3424.

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Abstract Molecular glue degraders have emerged as a powerful class of small-molecule therapeutics, as demonstrated by the clinical successes of thalidomide analogs in the treatment of hematological malignancies. These small molecules act by recruiting ubiquitin ligases to disease-relevant proteins, resulting in neosubstrate ubiquitination and degradation. To date, only a small number of ubiquitin ligase - neosubstrate interactions have been exploited by molecular glue degraders, limiting the targeting scope of this therapeutic modality. Covalent chemistry, which confers high binding affinity a

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Zhang, Zhimin, Min Chen, Cancan Cai, et al. "Abstract 383: Discovery of potent, selective, and orally bioavailable GSPT1 molecular glue degraders (MGDs) for the treatment of MYC-driven tumors." Cancer Research 85, no. 8_Supplement_1 (2025): 383. https://doi.org/10.1158/1538-7445.am2025-383.

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Background: MYC is a well-recognized proto-oncogene, which is mutated and overexpressed in various tumors. However, MYC is challenging to target due to its disordered structure and nuclear localization. There is a significant unmet clinical need for the effective treatments for MYC-driven tumors. G1 to S phase transition 1 (GSPT1) is a translation termination factor regulating protein expression. GSPT1 is involved in many biological processes, including the regulation of cell proliferation, migration, growth cycle and apoptosis. MYC-driven tumors are highly dependent on protein translation to

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Santiesteban, Daniela Y., Aundrietta D. Duncan, Nadeem Q. Mirza, et al. "Abstract 524: SP-3164, a novel ikaros and aiolos molecular glue degrader with preclinical activity in non-Hodgkin lymphomas." Cancer Research 83, no. 7_Supplement (2023): 524. http://dx.doi.org/10.1158/1538-7445.am2023-524.

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Abstract Background: Relapsed or refractory (R/R) non-Hodgkin lymphomas (NHLs) continue to be an area of high unmet need with patients seeking novel, chemotherapy-free options. One modality that has demonstrated success in NHLs is targeted protein degradation (TPD). Lenalidomide (LEN), a molecular glue degrader, is approved for treatment of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and other NHLs. Avadomide (AVA), a next-generation molecular glue, showed compelling clinical NHL activity. Notably, because of rapid in vivo interconversion between the (R)- and (S)-enantiome

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Dhruv, Harshil D., Donna McEachern, Longchuan Bai, et al. "Abstract 2656: The selective IKZF2 molecular glue degrader, PVTX-405, counters Treg immune suppression,shows significant tumor growth delay as single agent and synergistic response with immune checkpoint therapies (ICTs)." Cancer Research 84, no. 6_Supplement (2024): 2656. http://dx.doi.org/10.1158/1538-7445.am2024-2656.

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Abstract Immunosuppressive regulatory T-cells (Tregs) are key modulators of tumor immune evasion and resistance to immune checkpoint therapies (ICTs). IKZF2 (Helios) is a transcription factor that is selectively expressed by Treg and has been shown to be essential for maintaining function and stability of Tregs in the face of inflammatory conditions that include autoimmune disease as well as cancer. Here we describe the discovery of PVTX-405, a potent and selective IKZF2 molecular glue degrader (DC50=6.3 nM). Our molecular glue degrader promotes a productive ternary complex with the E3 ubiquit

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Ting, Pamela Y., Sneha Borikar, John Ryan Kerrigan, et al. "A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction." Science 385, no. 6704 (2024): 91–99. http://dx.doi.org/10.1126/science.adk6129.

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Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate disease complications and has been intently pursued. However, safe and effective small-molecule inducers of HbF remain elusive. We report the discovery of dWIZ-1 and dWIZ-2, molecular glue degraders of the WIZ transcription factor that robustly induce HbF in erythroblasts. Phenotypic screening of a cereblon (CRBN)–biased chemical library revealed WIZ as a previously unknown repressor of HbF. WIZ degradation is

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Palacino, James, Chen Bai, Yong Yi, et al. "Abstract 3933: ORM-5029: A first-in-class targeted protein degradation therapy using antibody neodegrader conjugate (AnDC) for HER2-expressing breast cancer." Cancer Research 82, no. 12_Supplement (2022): 3933. http://dx.doi.org/10.1158/1538-7445.am2022-3933.

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Abstract Targeted protein degradation (TPD) molecules, including IMiD-based molecular glues and heterobifunctional degraders have expanded the breadth of therapeutic options through both their catalytic mechanism of action and ability to degrade previously “undruggable” target proteins. To increase the efficacy vs. tolerability window of protein degradation and improve drug delivery we combine the catalytic approach of targeted protein degradation with the precision of tumor targeting therapeutic antibodies. Here, we describe the development of ORM-5029, a highly potent and selective GSPT1 deg

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Ma, Xiaolei. "Discovery and structural characterization of a VHL-mediated molecular glue degrader targeting cysteine dioxygenase." Acta Crystallographica Section A Foundations and Advances 77, a1 (2021): a245. http://dx.doi.org/10.1107/s0108767321097543.

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Słabicki, Mikołaj, Zuzanna Kozicka, Georg Petzold, et al. "The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K." Nature 585, no. 7824 (2020): 293–97. http://dx.doi.org/10.1038/s41586-020-2374-x.

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Tiedt, Ralph, Martin Schillo, Arnaud Osmont, et al. "Abstract 3294: The GSPT1 molecular glue degrader MRT-2359 is active against prostate cancer." Cancer Research 84, no. 6_Supplement (2024): 3294. http://dx.doi.org/10.1158/1538-7445.am2024-3294.

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Abstract We have previously described our GSPT1 molecular glue degrader MRT-2359, which was optimized to achieve preferential antiproliferative activity in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) expressing high N-MYC or L-MYC mRNA. A clinical trial with this new drug candidate is ongoing (NCT05546268). Here, we present pre-clinical profiling of MRT-2359 across hundreds of cancer cell lines representing multiple cancer types, aiming at identifying other cancers where preferential sensitivity is associated with high expression of a MYC family member. These studies s

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Kong, Ran, Shi Feng, Cong Wang та ін. "A Highly Selective and Orally Bioavailable CK1α Molecular Glue Degrader Targets B-Cell Lymphoma Cells". Blood 144, Supplement 1 (2024): 956. https://doi.org/10.1182/blood-2024-208315.

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Therapeutics for aggressive and high-risk lymphomas such as activated B-cell-like subtype of diffuse large B-cell lymphoma (ABC-DLBCL), which often develop resistance to treatment, remain unmet. Lenalidomide's clinical efficacy in del(5q) myelodysplastic syndrome is linked to CK1α degradation, though it more potently degrades IKZF1/3. Here, we report the discovery of a highly selective and orally active CK1α molecular glue degrader with strong activity against B-cell lymphomas, including those with acquired genetic resistance to BTK inhibitors. To identify molecular glues other than degraders

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Ford, Michael J., Ravi Amunugama, David L. Allen, and Richard C. Jones. "Abstract 7027: Mass spectrometry-based proteomics for accelerating PROTAC and molecular glue drug discovery." Cancer Research 85, no. 8_Supplement_1 (2025): 7027. https://doi.org/10.1158/1538-7445.am2025-7027.

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Abstract Targeted protein degradation (TPD) platforms, including PROTACs and molecular glues, have revolutionized drug discovery as transformative therapeutic strategies. Recent advancements in mass spectrometry-based proteomics have dramatically improved assay speed and sensitivity, providing actionable insights into degradation profiles and drug efficacy on timescales compatible with discovery chemistry. This study evaluates the practical utility of advanced proteomic assays in supporting TPD research, focusing on their role in streamlining drug discovery pipelines. State-of-the-art proteomi

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Archibeque, Ivonne, Ken Dellamaggiore, Karen Rex, et al. "Abstract 6567: Affinity and cooperativity modulate ternary complex formation to drive degradation of SMARCA2." Cancer Research 84, no. 6_Supplement (2024): 6567. http://dx.doi.org/10.1158/1538-7445.am2024-6567.

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Abstract Small molecules that hijack the ubiquitin-proteasome system to degrade target proteins have gained traction as tools for chemical biology and as promising clinical candidates. Targeted degradation strategies encompass relatively large hetero-bifunctional small molecules (hSMs) that are built from target and effector ligands joined by a linker to much smaller molecular glues that have limited affinity for the target or effector proteins outside of a ternary complex. There is good reason for medicinal chemists to move from linkered hSMs toward glue-like scaffolds. Molecular glues can be

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Jo, Hyunsun, Hoon Choi, Hyemin Kim та ін. "Abstract 1642: Next trip: a promising CK1α-selective molecular glue degrader in MSS colorectal cancer". Cancer Research 85, № 8_Supplement_1 (2025): 1642. https://doi.org/10.1158/1538-7445.am2025-1642.

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Abstract Casein kinase 1α (CK1α) is a serine/threonine kinase that plays a critical role in cellular homeostasis. In previous studies, CK1α promotes p53 inactivation by regulating MDM2 and MDMX, and this mechanism may represent a promising anticancer target Indeed, many studies have been reported recently on the development of CK1α inhibitors and degraders as anticancer agents. We recently developed PIN5018, a selective CK1α inhibitor, and reported that it exhibits promising anticancer activity in acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Interestingly, PIN5018 showed an

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Au, CheukMan C., Catrina Estrella, Prerna Vatsa, et al. "Abstract 1231: First-in-class AR-V7/AR-fl small molecule molecular glue degrader for prostate cancer treatment." Cancer Research 84, no. 6_Supplement (2024): 1231. http://dx.doi.org/10.1158/1538-7445.am2024-1231.

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Abstract Metastatic castration resistance prostate cancer (mCRPC) is a lethal disease due to the development of treatment to androgen receptor (AR) signaling inhibitors (ARSi) and taxane chemotherapy. Treatment resistance occurs partly due to the expression of AR splice variants that lack the ligand binding domain (LBD) and are constitutively active in the nucleus. AR-V7 is the most prevalent variant conferring clinical resistance to both ARSi and taxanes. Currently, there is no selective AR-V7 inhibitor leaving patients with limited therapeutic options. Thus, the development of selective AR-V

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Liu, Yuan, Mads B. Larsen, Bo Lin, et al. "Abstract 6071: Identification of a molecular glue degrader targeting the full-length AR and AR-V7 splice variant." Cancer Research 84, no. 6_Supplement (2024): 6071. http://dx.doi.org/10.1158/1538-7445.am2024-6071.

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Abstract Prostate cancer is the most common cancer in males and the fifth leading cause of cancer mortality worldwide. A variety of therapeutic approaches exist including steroid synthesis inhibitors and next-generation ligand binding domain (LBD) antagonists [e.g., enzalutamide (Enza)]. However, these approaches are only effective against tumors bearing the full-length androgen receptor (AR-FL). In the course of their disease, many patients acquire androgen receptor splice variant 7 (AR-V7), a mutant form of the receptor which lacks the LBD and is constitutively activated. To date, no effecti

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Liu, Jun, Ziyang Shen, Yanhua Dong, et al. "A Novel Small Molecule Drug-Based Approach for Treating Beta-Globinopathies." Blood 144, Supplement 1 (2024): 172. https://doi.org/10.1182/blood-2024-211753.

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Beta-globinopathies, such as β-thalassemia and sickle cell disease, present significant global health challenges. Existing treatments, including γ-globin inducers, blood transfusions, gene therapies, and bone marrow transplantation, face hurdles of cost, efficacy, and tolerability. In addition to the known function of BCL11A, recent research underscores the crucial role of ZBTB7A/LRF, another transcriptional factor, in suppressing γ-globin during the erythroid globin switch. While transcription factors have historically been deemed “undruggable”, recent advancements in therapeutic modalities,

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Dillon, Christian. "Abstract 398: Systematic identification and translation of novel targeted protein degradation mechanisms." Cancer Research 85, no. 8_Supplement_1 (2025): 398. https://doi.org/10.1158/1538-7445.am2025-398.

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Abstract The rise of Targeted Protein Degradation (TPD) is rapidly changing perceptions about therapeutic target druggability and drug design. However, the majority of degraders in clinical and preclinical development rely on the recruitment of a single E3 ligase, Cereblon, highlighting a pressing need to identify and translate novel mechanisms. Moreover, the discovery of molecular glue degraders is hampered by the prevailing serendipitous nature of their discovery. To unlock the potential of this modality we have developed proprietary cell-based screening platforms, SITESEEKER® and GlueSEEKER

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Dillon, Christian. "Abstract 6052: Systematic identification of novel targeted protein degradation mechanisms using SITESEEKER® technology." Cancer Research 84, no. 6_Supplement (2024): 6052. http://dx.doi.org/10.1158/1538-7445.am2024-6052.

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Abstract The rise of Targeted Protein Degradation (TPD) is rapidly changing perceptions about therapeutic target druggability and is rewriting many preconceived notions on drug design. However, the majority of monovalent molecular glue and heterobifunctional degraders in clinical and preclinical development rely predominantly on the recruitment of a single E3 ligase, Cereblon. Arising resistance, toxicities and restricted Protein-of-Interest scope may limit clinical potential, highlighting the need to uncover novel TPD mechanisms. To expand the potential of this modality, we have developed SIT

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Kim, H., S. Park, J. Park, B. S. Cho та H. Jo. "61 (PB049): A Promising CK1α-selective Molecular Glue Degrader for p53 Reactivation in Hematological and Solid Tumors". European Journal of Cancer 211 (жовтень 2024): 114588. http://dx.doi.org/10.1016/j.ejca.2024.114588.

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Park, Seulki, Akshay D. Takwale, Ji-Eun Lee, et al. "Discovery of a novel molecular glue degrader targeting GSPT1/2 with a non-IMiD-based CRBN binder." European Journal of Medicinal Chemistry 291 (July 2025): 117642. https://doi.org/10.1016/j.ejmech.2025.117642.

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Gavory, Gerald, Mahmoud Ghandi, Anne-Cecile d’Alessandro, et al. "Abstract 3929: Identification of MRT-2359 a potent, selective and orally bioavailable GSPT1-directed molecular glue degrader (MGD) for the treatment of cancers with Myc-induced translational addiction." Cancer Research 82, no. 12_Supplement (2022): 3929. http://dx.doi.org/10.1158/1538-7445.am2022-3929.

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Abstract Myc transcription factors are well-established drivers of human cancers. However, despite being amongst the most frequently mutated, translocated and overexpressed oncogenes, no therapy targeting the Myc family members directly has been developed to date. To sustain uncontrolled cell proliferation and tumor growth, Myc-driven cancers are known to be addicted to protein translation. This addiction creates a dependency on critical components of the translational machinery providing in turn a unique opportunity for therapeutic intervention. We hypothesized that targeting the translationa

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Yang, Jiuling, Yangbing Li, Angelo Aguilar, Zhaomin Liu, Chao-Yie Yang, and Shaomeng Wang. "Simple Structural Modifications Converting a Bona fide MDM2 PROTAC Degrader into a Molecular Glue Molecule: A Cautionary Tale in the Design of PROTAC Degraders." Journal of Medicinal Chemistry 62, no. 21 (2019): 9471–87. http://dx.doi.org/10.1021/acs.jmedchem.9b00846.

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Thompson, Peggy A., Pengyu Yang, Xiaoming Li, et al. "Abstract 1111: Identification of selective IKZF2 degraders that reprogram suppressive regulatory T cells in solid tumors." Cancer Research 82, no. 12_Supplement (2022): 1111. http://dx.doi.org/10.1158/1538-7445.am2022-1111.

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Abstract Targeted protein degradation (TPD) using the endogenous Ubiquitin Proteasome System (UPS) is a rapidly growing drug discovery strategy to eliminate pathogenic proteins. Molecular glues are small molecules that promote a novel interaction between a protein of interest with an E3 ubiquitin ligase leading to proximity induced protein degradation. This has enabled targeting undruggable proteins, such as the zinc-finger transcription factor Helios (IKZF2), that have no known small molecule binding pocket. Despite recent clinical breakthroughs in checkpoint blockade in treating solid tumors

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Park, Seulki, Jeong Hee Moon, Gaseul Lee, Hyun Jin Kim, Jeong-Hoon Kim, and Jong Yeon Hwang. "Abstract 4512: Discovery of highly potent, selective, and orally bioavailable IKZF2 degrader and its anti-tumor activity in syngeneic mouse models." Cancer Research 84, no. 6_Supplement (2024): 4512. http://dx.doi.org/10.1158/1538-7445.am2024-4512.

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Abstract Molecular glue degraders (MGDs) are emerging as innovative therapeutic modalities, owing to their efficacy in targeting previously undruggable targets. MGDs induce close proximity between the target protein and E3 ligase, resulting in the degradation of the target protein. In the wake of the remarkable success of PD-1/PD-L1 inhibitors, various approaches to modulate the activity of regulatory T cells (Tregs) activity have been explored. Tregs represent the primary immune suppressor and significantly impede antitumor immune responses. IKZF2, a marker of stable suppressive Treg, is esse

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Liu, J., Y. Senussi, A. Melkonian, D. R. Walt, and L. Chai. "Development of a Companion Diagnostic for a Targeted Protein Degradation Therapy: Ultrasensitive and Minimally-Invasive Detection of SALL4 Oncoproteins for Therapeutic Monitoring." American Journal of Clinical Pathology 160, Supplement_1 (2023): S89—S90. http://dx.doi.org/10.1093/ajcp/aqad150.198.

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Abstract Introduction/Objective Spalt-Like Transcription Factor 4 (SALL4), a member of the SALL family, is a regulator of embryonic stem cell development that plays a crucial role in cell renewal and proliferation. SALL4 expression is normally repressed in most adult organs but is reactivated in a multitude of cancers and upon treatment with hypomethylating agents (HMA). Research in the past 20 years established SALL4 as a novel, druggable cancer target. SALL4 targeting therapies (inhibitors and degraders) are under pre-clinical development. There are currently no FDA/CLIA approved SALL4 diagn

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Lampropoulou, Alexandra, Christos Siokatas, Nikolaos Plakas, Aikaterini-Maria Petrova, Vasiliki Sarli, and Constantin Tamvakopoulos. "Abstract LB193: Developing protein degraders to target the “undruggable” MYC." Cancer Research 85, no. 8_Supplement_2 (2025): LB193. https://doi.org/10.1158/1538-7445.am2025-lb193.

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Abstract Despite significant progress in cancer treatment, certain cancers remain difficult to target, particularly when aberrant expression of the c-MYC protein is involved, a target considered "undruggable" due to its disordered structure and lack of binding sites. Efforts to generate small molecule MYC inhibitors (Stellas et al 2014, Truica et al 2021) have been remarkable but have not yet resulted into MYC inhibitors available to the clinician. A promising alternative approach to targeting c-MYC and other “undruggable” targets is the discovery of PROteolysis-TArgeting Chimeras (PROTACs), h

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Balog, Aaron. "Abstract ND05: The discovery of BMS-986449, a highly potent and selective degrader of the transcription factors Helios (IKZF2) and Eos (IKZF4) for the treatment of solid tumors." Cancer Research 85, no. 8_Supplement_2 (2025): ND05. https://doi.org/10.1158/1538-7445.am2025-nd05.

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Abstract Regulatory T (Treg) cell abundance in the tumor microenvironment is associated with poor responses to immunotherapies, such as nivolumab. The transcription factors Helios (IKZF2) and Eos (IKZF4) are abundantly expressed in Treg cells and contribute to the immunosuppressive phenotype associated with this T-cell subset. We and others have postulated that degradation of Helios and Eos could re-polarize Treg cells towards a less suppressive, more inflammatory phenotype that would result in an enhanced antitumor effector T cell response. This presentation will describe the discovery and ch

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Thompson, Peggy A., Pengyu Yang, Linette Yang, et al. "Abstract B37: PLX-4107, a selective IKZF2 degrader, reprograms suppressive regulatory T cells and demonstrates anti-tumor activity." Cancer Immunology Research 10, no. 12_Supplement (2022): B37. http://dx.doi.org/10.1158/2326-6074.tumimm22-b37.

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Abstract Immune checkpoint therapy has demonstrated durable clinical responses in multiple solid tumor types. Reduced clinical response to checkpoint therapy has been linked to the presence of potent immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment that contribute to tumor immune evasion. The transcription factor Helios (IKZF2) is a marker of highly suppressive Tregs and is required to maintain a stable, suppressive Treg cell phenotype in the inflammatory tumor microenvironment. Depletion of IKZF2 in Tregs results in both loss of suppressive activity and conversio

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Liu, Fei, Yunkai Zhang, Baiyun Wang, et al. "Abstract 7035: Targeting Ewing sarcoma with a novel RBM39 degrader: DNA damage repair pathway effects." Cancer Research 85, no. 8_Supplement_1 (2025): 7035. https://doi.org/10.1158/1538-7445.am2025-7035.

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Abstract Patients with metastatic Ewing Sarcoma have a five-year survival rate of 15-30%. For 30 years, there are limited approved therapies, including chemotherapy, radiotherapy and surgery, which are associated with significant morbidities and secondary cancers, supporting the need for new impactful therapies. Analysis of the RNA splicing factor RNA Binding Motif Protein 39 (RBM39) in the Cancer Target Discovery and Development (CTD2) Network showed that Ewing sarcoma cell lines are especially sensitive to RBM39 loss. Here we demonstrate effects on mediators of DNA damage repair in associati

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Cartwright Ph.D, A., F. Desai, S. Nguyen, et al. "P164 MRT-6160, a VAV1-directed molecular glue degrader, inhibits disease progression and inflammation in a T-cell transfer model of Colitis." Journal of Crohn's and Colitis 18, Supplement_1 (2024): i469. http://dx.doi.org/10.1093/ecco-jcc/jjad212.0294.

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Abstract Background VAV1 is an immune-restricted guanine nucleotide exchange factor critical for T-cell receptor (TCR) and B-cell receptor (BCR) signalling. The role of VAV1 in T-cells has been demonstrated in knockout mice, which exhibit decreased effector functions and resistance to autoimmune disease models, and in CRISPR-based screens, where VAV1 has been highlighted as a top hit among positive regulators of T-cell function. Until now, VAV1 has remained undruggable by conventional small molecules. MRT-6160 is a first-in-class molecular glue degrader that specifically targets VAV1 for prote

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Joo, Min Sung, JaeYung Lee, Joonhyung Lee, et al. "Abstract 3295: Pharmacological characterization of CYRS1542: A potent and orally available GSPT1 molecular glue degrader for the treatment of neuroendocrine solid cancer with a favorable safety profile." Cancer Research 84, no. 6_Supplement (2024): 3295. http://dx.doi.org/10.1158/1538-7445.am2024-3295.

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Abstract Neuroendocrine cancers (NECs) are relatively rare compared to other malignancies, but their clinical behavior can be exceptionally aggressive. Two particularly challenging subtypes of NECs, Small Cell Lung Cancer (SCLC) and Neuroendocrine Prostate Cancer (NEPC), are worthy of attention due to their rapid progression, limited treatment options, and high mortality rates. At the molecular level, SCLC and NEPCs necessitate the presence of TP53 and RB1 mutations (Beltran et al., 2016; George et al., 2015). The frequency of TP53 mutations in SCLC is particularly noteworthy, with studies con

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Shi, Haonan. "Molecular Glues and Molecular Glue Degraders: Mechanisms, Design, and Therapeutic Applications." Transactions on Materials, Biotechnology and Life Sciences 7 (December 24, 2024): 213–20. https://doi.org/10.62051/r1m5q711.

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Molecular glues and molecular glue degraders appear to be a fast-growing class of therapeutic agents that selectively modulate protein-protein potential interactions and can enhance the selective degradation of proteins. These small molecules are providing the possibility to target proteins that previously thought to be very challenging or inaccessible that are involved in a host of diseases. The present review focuses on describing the basic concepts of molecular glues and the rationale behind the interactions and the general concept that drives their design. Special attention is paid to thei

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Gavory, Gerald, Mahmoud Ghandi, Anne-Cecile d’Alessandro, et al. "Abstract 3449: Development of MRT-2359, an orally bioavailable GSPT1 molecular glue degrader, for the treatment of lung cancers with MYC-induced translational addiction." Cancer Research 83, no. 7_Supplement (2023): 3449. http://dx.doi.org/10.1158/1538-7445.am2023-3449.

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Abstract MYC transcription factors are well-established drivers of human cancers but despite being amongst the most frequently altered oncogenes, no approved therapy targeting MYC-driven tumors has been developed to date. MYC-driven cancers are known to be addicted to protein translation. This addiction creates a dependency on critical components of the translational machinery providing in turn a unique opportunity for therapeutic intervention. We hypothesized that targeting the translation termination factor GSPT1, a key regulator of protein synthesis, would constitute a vulnerability for MYC

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Jimenez, Carmen, Sophie Peng, Rama Krishna Narla та ін. "BMS-986397, a First-in-Class Molecular Glue Degrader of Casein Kinase 1α (CK1α) for the Treatment of Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HR-MDS) Harboring Functional TP53". Blood 144, Supplement 1 (2024): 4142. https://doi.org/10.1182/blood-2024-209924.

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Introduction: The Casein Kinase 1α (CK1α) gene resides on chromosome 5q and has haploid status in del5q MDS (Myelodysplastic Syndrome). Lenalidomide is a weak, but significant degrader of CK1α, and has clinical efficacy in del5q MDS relative to non-del5q MDS. Therefore, development of a strong degrader of CK1α that may have activity in myeloid malignancies irrespective of 5q status is warranted. We identified BMS-986397 as a potent, specific, oral CELMoD molecular glue degrader of CK1α. Here, we present preclinical evidence of p53-dependent efficacy of BMS-986397 in AML (Acute Myeloid Leukemia

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Cartwright, Adam N., Foram Desai, Laura Roditi, et al. "Tu1727 MRT-6160, A VAV1-DIRECTED MOLECULAR GLUE DEGRADER, INHIBITS DISEASE PROGRESSION IN A T-CELL TRANSFER MEDIATED MURINE COLITIS MODEL CONCOMITANT WITH REDUCED CALPROTECTIN EXPRESSION." Gastroenterology 166, no. 5 (2024): S—1396. http://dx.doi.org/10.1016/s0016-5085(24)03664-3.

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DiMartino, Jorge F., Peggy Thompson, Yujun Huang, Kevin Freeman-Cook, Christine Farrell, and Pengyu Yang. "Abstract CT150: A first in humans trial of PLX-4545, a molecular glue degrader of IKZF2, in healthy volunteers, shows pharmacologic modulation of Tregs at well-tolerated doses." Cancer Research 85, no. 8_Supplement_2 (2025): CT150. https://doi.org/10.1158/1538-7445.am2025-ct150.

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Abstract Background: PLX-4545 is a potent and selective, orally bioavailable, cereblon-mediated molecular glue degrader of IKZF2 (Helios), a lineage defining transcription factor for immunosuppressive Treg cells, that induces loss of Treg suppressive function and acquisition of an effector T cell (Teff)-like phenotype. In pre-clinical xenograft models, PLX-4545 demonstrates single-agent anti-tumor activity comparable to PD-1 inhibition as well as combination benefit with PD-1 inhibitors. This study evaluated the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of PLX-4545 in healthy adu

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