Abstract 1743: QLS1209, A highly potent and selective PKMYT1 inhibitor demonstrates activity in tumors with CCNE1Amp and/ or FBXW7LoF mutations
Authors: Yuxing Zhang, Jiasheng Fu, Rongyan Wang, Jianping Chen, Changliang He, Junguo Hao, Xinrui Shao, Ling Li, Hua Qin, Guangyue Lei, Ping Chen, Dong Yang, Xinghua Cheng, Qingmei Zheng, Zheng Wang, Guqin Shi, Wenyuan Qian, Daqing Sun, Weimei Sun, Weikang Tao
Journal: Cancer Research (2025)

Abstract Cell cycle checkpoints serve as cellular critical safeguard mechanisms that ensure orderly progression through the cell cycle. PKMYT1, a membrane-associated kinase, functions as a negative regulator of CDK1 activity by phosphorylating CDK1 at the Thr14 residue. This enzyme is frequently overexpressed in a variety of cancers. Recent studies suggest that cancer cells harboring CCNE1 amplification (CCNE1Amp) and/or FBXW7 loss-of-function (FBXW7LoF) mutations are particularly relying on PKMYT1 for orderly entry to mitosis. As a result, inhibition of PKMYT1 can lead to premature mitotic entry, inducing DNA damage, and triggering mitotic catastrophe. CCNE1Amp is a common genetic alteration found across a spectrum of cancer types, with particular prevalence in gynecological malignancies. Elevated levels of cyclin E are linked to genomic instability, whole-genome doubling, and resistance to existing therapeutic interventions. FBXW7, a tumor suppressor gene, is frequently mutated in various cancers, including colorectal and ovarian serous carcinoma. Loss of FBXW7 function is recognized as an independent prognostic factor, significantly correlating with tumor cell resistance to chemotherapy and unfavorable disease outcomes. Moreover, FBXW7 acts as an E3 ubiquitin ligase for cyclin E, potentially leading to increased levels of cyclin E through post-translational mechanisms. QLS1209, an orally bioavailable, potent, and selective inhibitor of PKMYT1 was discovered and evaluated preclinically. QLS1209 exhibited single-digit nanomolar potency in inhibiting PKMYT1's enzymatic activity and demonstrated approximately 30-fold selectivity over its paralogue Wee1. QLS1209 potently suppressed phosphorylation of CDK1 at Thr14, with a minimal impact on Tyr15. QLS1209 was well tolerated and demonstrated anti-tumor activity in CCNE1Amp HCC1569 and OVCAR3 xenograft models in vivo, it also showed enhanced efficacy when combined with Gemcitabine. In a gastric patient-derived xenograft (PDX) model harboring an FBXW7LoF mutation, QLS1209 dose-dependently inhibited tumor growth, with higher dose leading to tumor regression. QLS1209 exhibits excellent pharmacokinetic profile, and promising in vitro ADME properties, along with a favorable safety profile. IND enabling studies are currently underway and are expected to be completed by the end of 2024. Collectively, these findings highlight the promising potential of QLS1209 as a therapeutic strategy, either as monotherapy or in combination with other anti-cancer therapies, for a variety of cancer types characterized by CCNE1Amp and/ or FBXW7LoF mutations. Citation Format: Yuxing Zhang, Jiasheng Fu, Rongyan Wang, Jianping Chen, Changliang He, Junguo Hao, Xinrui Shao, Ling Li, Hua Qin, Guangyue Lei, Ping Chen, Dong Yang, Xinghua Cheng, Qingmei Zheng, Zheng Wang, Guqin Shi, Wenyuan Qian, Daqing Sun, Weimei Sun, Weikang Tao. QLS1209, A highly potent and selective PKMYT1 inhibitor demonstrates activity in tumors with CCNE1Amp and/ or FBXW7LoF mutations [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 1743.