Abstract LB036: Characterization of BLU-448: A potent and selective degrader of CDK4 for the treatment of HR+/HER2- breast cancers

Abstract Background: Cyclin-dependent kinase 4 (CDK4) plays a key role in the proliferation of HR+/HER2- breast cancer cells, driving progression into S phase of the cell cycle. Small molecule inhibitors targeting CDK4/6 have become a cornerstone of treatment for HR+/HER2- breast cancer. However, first-generation CDK4/6 inhibitors demonstrate no to minimal selectivity for CDK4 over CDK6, resulting in hematological abnormalities associated with CDK6 inhibition, which is dose-limiting and hinders maximal efficacy. These clinical side-effects are well recapitulated in preclinical models: inducible deletion of CDK6 in adult mouse hematopoietic cells leads to neutropenia, whereas deletion of CDK4 does not. Genetic dependency data (DepMap) demonstrate that the majority of HR+/HER2- breast cancer cell lines rely on CDK4, but not CDK6, for cellular proliferation. Therefore, selective targeting of CDK4 can inhibit HR+/HER2- breast cancer growth while minimizing the CDK6-driven side effects. While a number of second-generation investigational CDK4 inhibitors offer improved selectivity over CDK6, neutropenia remains an adverse effect observed in early clinical trials. We have taken the approach to develop a potent and highly selective CDK4 degrader with minimal activity against the highly homologous CDK6 kinase. Results: Our efforts led to the identification of a development candidate, BLU-448, which is a potent, orally bioavailable, kinome-sparing degrader of CDK4, with superior selectivity over CDK6. The molecule shows weak intrinsic binding potency for CDK4 yet forms a tighter ternary complex between CDK4 and E3 ligase cereblon, resulting in rapid and robust degradation of CDK4 protein over CDK6. In HR+/HER2- breast cancer cell lines, BLU-448 leads to potent and sustained phospho-RB inhibition, sustained G1 cell cycle arrest, strong suppression of E2F target genes, and inhibition of cell proliferation. Importantly, we observe markedly enhanced selectivity for growth inhibition in breast cancer cell lines vs the neutropenia assays. Finally, BLU-448 has demonstrated robust and durable in vivo anti-tumor activity in preclinical models of breast cancer following oral administration. Conclusion: With its remarkable potency in driving CDK4 degradation and superior selectivity over CDK6, BLU-448 holds promise as a potential best-in-class treatment for HR+/HER2- breast cancers —and possibly beyond. Acknowledgements: We thank Percy Carter for his leadership and strong support on this CDK4 degrader program at Blueprint Medicines. We are thankful to members of VantAI for their technical assistance with induced proximity drug discovery. Citation Format: Zhihu (Jeff) Ding, Xiang Liu, Barbara K. Robens, Jeff Keats, Suzanne Spong, Fereidoon Daryaee, Michael R. Wasserman, Benjamin Barlock, Jian Guo, James Baker, Kenneth Kearney, Gramoz Kondakci, Camila Medrano-Trochez, Christophe Lemetre, Emily Erickson, Hana von der Linden, Dean Zhang, Sheng Sun, Rentian Wu, Lakshimi Muthuswamy, Jie Ge, Luis Torres, Kevin Barvian, Thiwanka Mudiyanselage, Winston L. Chow, Deborah G. Conrady, Yunxing (Stella) Li, Xavier Fradera, Yinghui Dai, Caitlin Kinkema, Jason Brubaker, Robert Meissner, Thomas A. Dineen, Chiara Conti, Kerrie Faia, Scott Ribich. Characterization of BLU-448: A potent and selective degrader of CDK4 for the treatment of HR+/HER2- breast cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB036.