Abstract C112: ACR-2316 is a novel, differentiated, clinical-stage WEE1/PKMYT1 inhibitor designed by Acrivon’s Generative Phosphoproteomics AP3 Platform for optimal pro-apoptotic pathway effects in tumor cells resulting in superior preclinical activity

作者：Portia Lombardo, Anna-Maria Alves, Martina Pasetto, Mohamed Eldeeb, Zachary Best, Reina Improgo, Nina Lipjankić, Subodh Kumar, Ruban Cornelius, Kate Rappard, Uthira Muralitharan, Valentina Siino, Ignacio Arribas Díez, William K. Dahlberg, Shahrzad Rafiei, Kailash Singh, Ayesha Murshid, Joelle Baddour-Sousounis, Magnus E. Jakobsson, Michail Shipitsin, Helén Nilsson, Caroline Wigerup, Lei Shi, David A. Proia, Kristina Masson, Peter Blume‐Jensen · 发表于：Molecular Cancer Therapeutics · 年份：2025 · DOI：10.1158/1535-7163.targ-25-c112 · 被引用次数：1 · 研究领域：Protein Degradation and Inhibitors

Abstract Introduction: ACR-2316 is an internally discovered, clinical stage, potentially first- and best-in-class WEE1/PKMYT1 (MYT1) inhibitor specifically designed using Acrivon’s Predictive Precision Proteomics (AP3) platform. Here, we delineate the differentiated profile by which ACR-2316 achieves superior preclinical efficacy compared to benchmark WEE1 or MYT1 inhibitors. Methods: Intracellular global pathway activity modulation, kinase activity, and target engagement (TE) were assessed by mass-spectrometry based AP3, AlphaLISA, immunofluorescence, and Western blot (WB). Cell viability was assessed by CellTiter Glo (CTG). MYT1 stably overexpressing cells were generated by selection following transfection of MYT1 cDNA. Replication stress, DNA damage, and cell death were assessed by flow cytometry, CTG, and live cell imaging. In vivo efficacy and TE were evaluated in a human cancer cell line-derived xenograft (CDX) model. Results: Through AP3 profiling, we previously uncovered WEE1 inhibitor-induced resistance mechanisms that were quenched by MYT1 inhibition. ACR-2316 was rationally designed using AP3 to suppress this resistance mechanism alongside potent WEE1 inhibition and robust activation of CDK1, CDK2, and PLK1, to induce potent tumor cell death. In cellular TE assays, ACR-2316 displayed more potent WEE1 TE than all benchmark WEE1 inhibitors (azenosertib, adavosertib, Debio0123), while simultaneously targeting MYT1. The impact of MYT1 TE was evidenced by a >3X l...