Ralph Tiedt

Abstract B044: Targeting the “undruggable” oncogene CCNE1 using a molecular glue degrader in CCNE1 amplified cancers

William Tahaney, Yimao Liu, Ahmed Abdullah, Vittoria Massafra et autres

Abstract Using our QuEENTM molecular glue degrader (MGD) discovery engine that integrates biochemical and cellular assays with in silico modeling, we identified and optimized MGDs that induce proteasomal degradation of cyclin E1 (CCNE1) as a therapeutic strategy for CCNE1-amplified cancers. We generated …

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Abstract PR003: Targeting the “undruggable” oncogene CCNE1 using a molecular glue degrader in CCNE1 amplified cancers

William Tahaney, Yimao Liu, Ahmed Abdullah, Vittoria Massafra et autres

Abstract Using our QuEENTM molecular glue degrader (MGD) discovery engine that integrates biochemical and cellular assays with in silico modeling, we identified and optimized MGDs that induce proteasomal degradation of cyclin E1 (CCNE1) as a therapeutic strategy for CCNE1-amplified cancers. We generated …

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Abstract 6778: Selective targeting of CCNE1 using molecular glue degraders for the treatment of CCNE1 amplified cancers

William M. Tahaney, Yimao Liu, Ahmed Abdullah, Vittoria Massafra et autres

Abstract Cyclin E1 (CCNE1) is a critical driver of cell cycle progression and cell proliferation. It acts as the regulatory subunit for the CCNE1-CDK2 holoenzyme, which coordinates cell cycle progression through the G1/S phases and effectively drives cell proliferation via RB phosphorylation …

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A phase 1/2 study of MRT-2359, a highly selective oral GSPT1 molecular glue degrader (MGD), in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) harboring AR ligand binding domain (LBD) mutations.

Rahul Atul Parikh, Benjamin Herzberg, Mark N. Stein, Shumei Kato et autres

161 Background: Progression to mCRPC is driven by numerous mechanisms including emergence of AR LBD mutations that reactivate the AR pathway and blunt response to hormone therapies including novel hormonal agents (NHA). MRT-2359, an orally bioavailable MGD that selectively degrades the translation …

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Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry

Stefano Annunziato, Chao Quan, Etienne J. Donckèle, Ilaria Lamberto et autres

Molecular glue degraders (MGDs) are small-molecule compounds that divert E3 ligases to degrade nonnatural substrates called neosubstrates. Clinically effective MGDs bind cereblon (CRBN), a substrate receptor of the Cullin 4–RING E3 ubiquitin ligase (CRL4CRBN), and recruit neosubstrates to an MGD-induced neosurface on …

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Mining the CRBN target space redefines rules for molecular glue–induced neosubstrate recognition

Georg Petzold, Pablo Gaínza, Stefano Annunziato, Ilaria Lamberto et autres

The CRL4 CRBN E3 ubiquitin ligase is the target of molecular glue degrader compounds that reprogram ligase specificity to induce the degradation of clinically relevant neosubstrate proteins. Known cereblon (CRBN) neosubstrates share a generalizable β-hairpin G-loop recognition motif that allows for the …

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Abstract P5-01-26: Selective Targeting of CDK2 Using Molecular Glue Degraders for the Treatment of HR-Positive/HER2-Negative Breast Cancer

Nina Ilic-Widlund, William M. Tahaney, Vasia Vafeiadou, Christelle Bianda et autres

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 …

Molecular surface mimicry enables CRBN to target G3BP2 for degradation

Stefano Annunziato, Chao Quan, Etienne J. Donckèle, Ilaria Lamberto et autres

Molecular glue degraders (MGDs) are small molecule compounds that repurpose the ubiquitin-proteasome system to induce degradation of challenging therapeutic targets. Clinically effective MGDs bind cereblon (CRBN), a substrate receptor of the Cullin-4/RING E3 ubiquitin ligase (CRL4CRBN), and impose a gain-of-function activity to …

Abstract LB422: Selective targeting of CDK2 using molecular glue degraders for the treatment of HR-positive/HER2-negative breast cancer

Sofia Gkountela, William M. Tahaney, Vasiliki Vafeiadou, Christelle Bianda et autres

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 …

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511LBA (PB-511) LBA Posters: Selective Targeting of Cyclin E1 Using Molecular Glue Degraders in CCNE1 Amplified Solid Malignancies

Nina Ilic-Widlund, W. Tahaney, Yun Liu, S. Gkountela et autres

Capmatinib plus nivolumab in pretreated patients with EGFR wild-type advanced non–small cell lung cancer

Enriqueta Felip, Giulio Metro, Daniel Shao-Weng Tan, Juergen Wolf et autres

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Abstract 3294: The GSPT1 molecular glue degrader MRT-2359 is active against prostate cancer

Ralph Tiedt, Martin Schillo, Arnaud Osmont, Débora Bonenfant et autres

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 …

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