Abstract 3021: Discovery of a novel and selective CDK2 inhibitor for targeted cancer therapy

Targeted inhibition of CDK2 presents a promising therapeutic strategy for breast cancer patients who experience disease progression following CDK4/6-based therapies. In addition, CDK2 hyperactivity or CCNE1 amplification drives the progression of many cancer types, making it an attractive target. However, developing CDK inhibitors is often complicated by toxicities resulting from off-target inhibition of other CDK family members, particularly CDK1 and CDK9, which are essential for normal cell proliferation and survival. Achieving selectivity for CDK2 is therefore crucial to maximize therapeutic efficacy while minimizing adverse effects, enabling a broader therapeutic window in clinical applications. Here, we present VB18214 as a novel and selective CDK2 inhibitor. In biochemical assays, VB18214 demonstrated potent inhibition of the CDK2/cyclin E1 complex (IC50 = 0.6 nM) and exhibited 200-fold selectivity over CDK1/cyclin B1. Intracellular NanoBRET assays confirmed its high affinity for CDK2/cyclin E1 (IC50 = 3.8 nM), along with exceptional selectivity—124-fold over CDK1/cyclin B1, 12-fold over CDK4/cyclin D1, 94-fold over CDK6/cyclin D3, 334-fold over CDK7/cyclin H, and 1348-fold over CDK9/cyclin T1. In CCNE1-amplified OVCAR3 ovarian cancer cells, VB18214 effectively inhibited cell proliferation (IC50 = 18.5 nM). Compared to the clinically advanced CDK2 inhibitor PF-07104091, VB18214 demonstrated 5-fold greater potency in inhibiting CDK2 kinase activity, 16-fold higher affinity for CDK2 in NanoBRET assays, 2-fold greater selectivity over CDK1 in both biochemical and intracellular assays, and 9-fold higher antiproliferative activity in OVCAR3 cells.These findings position VB18214 as a potent and selective CDK2 inhibitor with significant potential for clinical development in cancers driven by CDK2/cyclin E dysregulation, as well as CDK4/6 treatment progressed mBC. More characterization data for VB18214 will be updated at the meeting. Citation Format: Douglas D. Fang, Yueqin Liu, Yang Liu, Wei Sha, Charles Z. Ding. Discovery of a novel and selective CDK2 inhibitor for targeted cancer therapy [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 3021.