Abstract 1742: Discovery and preclinical profiling of a novel PKMYT1 inhibitor, EVT-0003023, with high efficacy in late-stage, post-treatment non-small cell lung cancer models

Abstract Protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) is a negative regulator of CDK1 activity and has been identified as a putative synthetic lethal target in cancers which up-regulate cyclin E (CCNE1) or harbor mutations in genes such as FBXW7. We used our internal Frobenius platform to identify highly potent and differentiated inhibitors of PKMYT1 with exceptional selectivity over key off targets, including the Raf family and WEE1. Machine learning-driven optimization delivered a preclinical candidate compound, EVT-0003023, with best-in-class selectivity and a significantly improved pharmacokinetic profile in relevant animal models, and in vivo efficacy in CCNE1-high and FBXW7-mutated xenograft models. Compounds from this series were used to validate a differentiated biomarker for sensitivity to PKMYT1 inhibition in cellular and PDX-derived models, expanding the patient population treatable with PKMYT1 inhibitors into non-small cell lung cancer. Using clinical data, we demonstrated that this biomarker is significantly up-regulated in patients who have progressed on existing standard-of-care treatment, and demonstrated exceptional monotherapy activity for EVT-0003023 in PDX models reflecting this patient population, as well as tumor regression when combined with low doses of chemotherapy. Citation Format: Daniel Miller, Alfie Brennan, Jan Lanz, Oliver Vipond, Noah Harrison, James Aaronson, Anna Hercot. Discovery and preclinical profiling of a novel PKMYT1 inhibitor, EVT-0003023, with high efficacy in late-stage, post-treatment non-small cell lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1742.