Abstract 5775: When CDK meets CIP: Linking target engagement to functional outcomes in CDK2 molecular glue and CDK-TCIP

Abstract Background: Cyclin-dependent kinases (CDKs) orchestrate cell cycle progression and transcriptional control, and their dysregulation is a hallmark of cancer. While conventional CDK inhibitors have shown utility, emerging modalities such as molecular glues (MGs) and transcriptional/epigenetic chemical inducers of proximity (TCIPs) offer novel mechanisms to modulate or utilize CDK activity. CDK2 MG promote selective degradation of CDK2 complexes, whereas CDK9 TCIP induce proximity-driven transcriptional rewiring. The purpose of this study was to demonstrate linkage of target engagement to cellular outcomes across these two modalities, thereby establishing mechanistic insights for next-generation CDK therapeutics. Methods: We developed an integrated platform combining biophysical binder screening (Spectrum Shift, SPR, HTRF), cellular assays of CDK2 degradation and cell cycle control (proliferation, phospho-RB, flow cytometry), mechanism-of-action studies in CCNE-amplified and resistant models with drug combinations, CDK-TCIP engagement and transcriptional assays (NanoBRET, BCL6 reporter, qPCR), downstream functional profiling (viability, apoptosis, cancer cell panels, primary cell lines), and off-target evaluation by Western blotting, proteomics, and ICESTP safety panels. Results: CDK2 MG induced robust CDK2/CRBN ternary complex formation and degradation of CDK2, leading to reduced proliferation, decreased phospho-RB, and G1 arrest. CCNE amplification conferred heightened sensitivity, while palbociclib resistant cell lines revealed CDK2 MG as a potential strategy to overcome drug resistance. In contrast, CDK-TCIP stabilized ternary complexes that drove nuclear translocation and transcriptional activation, evidenced by BCL6 reporter activation and target qPCR upregulation. Functional assays demonstrate broad vulnerability across cancer cell panels, with apoptosis induction in select primary cell lines. Off-target profiling confirmed high selectivity, with minimal liabilities detected across proteomic and ICESTP safety screens. Conclusions: This study provides comprehensive profiling showing that CDK2 MGs and CDK-TCIPs achieve distinct biological outcomes through degradation versus transcriptional rewiring. By integrating biophysical, biochemical, and cellular analyses, we establish quantitative links between target engagement and phenotypic consequences. These findings define mechanistic frameworks for optimizing CDK-targeting modalities and inform rational design of selective, context-dependent interventions in oncology. Citation Format: Qing Xue, Zhu Meng, Xue Yang, Qian Wang, Lili Chai, Wei Liu, Tj (Tiejun) Bing, . When CDK meets CIP: Linking target engagement to functional outcomes in CDK2 molecular glue and CDK-TCIP [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 5775.