Abstract 1902: Comparative biochemical evaluation of small-molecule inhibitor efficacy on CDK/Cyclin complexes across diverse mammalian species.

Abstract Cyclin-dependent kinases (CDKs) and their associated cyclins are central regulators of cell cycle progression and transcriptional control. Dysregulation of CDK/Cyclin complexes is a hallmark of many cancers, driving uncontrolled proliferation and tumor development. Consequently, these complexes have become critical targets in oncology, with CDK4/6 inhibitors already established as a cornerstone in the treatment of e.g. hormone receptor-positive breast cancer and under investigation for other malignancies. Early preclinical development of CDK inhibitors relies on biochemical screening assays to identify small molecules capable of inhibiting CDK/Cyclin activity. These assays, frequently based on kinase activity measurements, enable high-throughput evaluation of compound libraries and provide essential insights into inhibitor potency and selectivity. These approaches are mandatory for rational drug design, guiding the optimization of lead compounds toward improved efficacy and reduced off-target effects. Despite their obvious limitations in predicting cellular and in vivo responses, these early screening strategies are instrumental in shaping the current generation of CDK- and other kinase-targeted therapeutics. In subsequent development stages, cellular and in vivo model systems are employed to validate inhibitor activity and assess pharmacodynamics and toxicity. Many of these models are based on non-human mammalian species, such as murine or primate systems. These studies are essential for bridging the gap between biochemical screening and clinical application, ensuring that candidate molecules demonstrate efficacy and safety before entering human trials. However, despite the importance of such data, it is rarely assessed in early biochemical screening whether results from human and non-human assays are consistent. Such early biochemical evaluation of potential differences in the effects of drug candidates on the kinase target from different species could generate valuable insights to select the most relevant cellular or in-vivo model systems for advanced drug-development. Here, we present comparative biochemical data for late-stage development or already approved CDK inhibitors tested against CDK/Cyclin complexes from human, rat, mouse, dog and primate origin, focusing on CDK4/CycD1. Notably, differential inhibitory potency was observed for several compounds, including palbociclib, which showed an approximately ten-fold difference in CDK4/CycD1 inhibition between human and murine enzymes. Citation Format: Andreas Gericke, Frank Totzke, Constance Rademann, Carolin Heidemann-Dinger, Daniel Mueller. Comparative biochemical evaluation of small-molecule inhibitor efficacy on CDK/Cyclin complexes across diverse mammalian species [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1902.