Abstract 5795: The discovery of BLU-020: A potent and selective degrader of CDK2 for the treatment of <i>CCNE1</i> aberrant cancers

Abstract Background: Cyclin E1 is the catalytic binding partner of CDK2, which becomes aberrantly activated when CCNE1 is amplified and overexpressed, driving tumorigenesis. Tumors with aberrant cyclin E1 expression are highly dependent on Cyclin E1/CDK2 activity, presenting a distinct therapeutic opportunity. Selective degradation of CDK2 may limit off-target CDK family-driven toxicities commonly associated with pan-CDK inhibitors. We highlight the discovery of BLU-020, a potent, CDK2-selective, and kinome-sparing investigational degrader of CDK2. Our efforts began with the design of CDK2-targeted heterobifunctional degraders leveraging Blueprint’s proprietary inhibitor library, resulting in the identification of several potent compounds with moderate selectivity. Subsequent modifications led to improvement on both CDK family selectivity and improvement on ADME properties of the lead series. With additional efforts to optimize the degraders for projected human dose, a development candidate, BLU-020, was identified. Results: BLU-020 is an orally bioavailable, kinome-sparing, CDK2-selective small molecule degrader that leads to potent and sustained pRb inhibition, significant and sustained G1 cell cycle arrest, strong and selective suppression of E2F targeted genes and inhibition of cell proliferation in CCNE1-aberrant CDK2-dependent tumor cell lines. In a screen against a panel of ∼100 tumor cell lines, BLU-020’s potency and selectivity was demonstrated by showing strong inhibition of CCNE1-aberrant tumor cells bearing the triple biomarker CCNE1 high/RB positive/p16 high, while completely sparing non-CDK2 dependent triple biomarker negative cell lines, with a selectivity ratio of over 500 fold. BLU-020 was able to sensitize tumor cell lines lacking p16 in combination with the CDK4/6i ribociclib. Finally, BLU-020 demonstrated robust and durable in vivo anti-tumor activity in preclinical models of CCNE1-amplified cancers such as OVCAR3 CDX model following once-daily oral administration. Conclusion: With its potency on CDK2 and improved selectivity over other CDK family members and the kinome compared to previous reported CDK2 agents, BLU-020 has best-in-class potential for CCNE1-aberrant ovarian cancers. Citation Format: Phil Ramsden, Dean Zhang, Maria Iliou, Suhasini Parimi, Jeff Keats, Maxine Chen, Lakshmi Muthuswamy, Guangyan Du, Fereidoon Daryaee, Ben Barlock, James Baker, Sue Spong, Ken Kearney, Gramoz Kondakci, Deborah G. Conrady, Stella Li, Xavier Fradera, Yinghui Dai, Tina Tran, Tom Dineen, Chiara Conti, . The discovery of BLU-020: A potent and selective degrader of CDK2 for the treatment of CCNE1 aberrant cancers [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 5795.