Abstract P4-12-29: ETX-197/BG-68501, a potential best-in-class potent, selective, oral, small molecule CDK2 inhibitor, has anti-tumor activity in cancer models with Cyclin E amplification or deficiency in the Retinoblastoma 1 gene

Abstract In a normal cell cycle, there is redundancy in the role of the cell-cycle dependent kinases (CDKs) in regulating G1/S phase transition. In cancer cells, the regulation of G1/S transition can be subverted by (a) amplification and elevated expression of Cyclin E (CCNE), or (b) mutation/loss of the Retinoblastoma 1 (RB1) gene. Cancer cells with these genomic alterations have been shown to exhibit profound sensitivity to CDK2 depletion, validating CDK2 as a potential therapeutic target. Here, we report the discovery and preclinical characterization of ETX-197, a highly potent and selective small molecule inhibitor of CDK2 enzymatic activity. Based on known ligand-CDK2 structures, ETX-197 is designed to induce previously unexplored interactions within the CDK2 ATP binding pocket leading to improved potency and selectivity compared to other known CDK2 inhibitors. ETX-197 is >100-fold selective against other kinases in the CDK family and the selectivity extends more broadly against 385 other kinases. The affinity of ETX-197 for CDK2 results in tight binding (slow off-rate) and high potency in pharmacodynamic modulation and anti-proliferative activity in vitro and in vivo. Treatment of CCNE-amplified cancer cells with ETX-197 results in concentration-dependent inhibition of pRB phosphorylation, G1/S phase cell-cycle arrest and cell proliferation. In addition, ETX-197 treatment phenocopies CDK2 genetic knock-down in cells, as revealed by bulk-RNA Seq analysis of CCNE-amplified or wild-type cells, confirming that the cellular activity of ETX-197 is on-target and highly selective. In mouse xenograft studies using CCNE-amplified ovarian cancer cell line (OVCAR-3) or patient-derived tumors, ETX-197 treatment causes dose-dependent tumor growth inhibition with excellent tolerability. Interestingly, in RB1-deficient small cell lung cancer cell lines, ETX-197 treatment results in G2/M cell cycle arrest, accumulation of DNA damage, and apoptosis. Xenograft studies with small cell lung cancer cell lines and patient-derived tumor cells also show significant tumor growth inhibition with ETX-197. Additionally, ETX-197 has single-agent efficacy in a breast cancer xenograft model that had acquired resistance to a CDK4/6 inhibitor. These data suggest that ETX-197 has the potential to be a best-in class CDK2 inhibitor for the treatment of cancer with CCNE amplification or RB1 deficiency, including breast cancer that has progressed on treatment with a CDK4/6 inhibitor because of these genomic alterations. Currently, ETX-197 is being clinically developed by BeiGene in a first-in-human (FIH), Phase 1a/1b study to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity in patients with advanced, nonresectable, or metastatic solid tumors (NCT06257264). Citation Format: Daliya Banerjee, Alexandra Weinheimer, Jingyan Gao, Fei Pang, Ying Lin, Raj Nagaraja, Yong Tang, Zipeng Fan, Zipeng Fan, Minghong Hao, Shengfang Jin, Tao Liu, Tai Wong. ETX-197/BG-68501, a potential best-in-class potent, selective, oral, small molecule CDK2 inhibitor, has anti-tumor activity in cancer models with Cyclin E amplification or deficiency in the Retinoblastoma 1 gene [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-12-29.