BLU-448

BLU-448 is a potent, orally bioavailable, and highly selective proteolysis-targeting chimera (PROTAC) designed to induce the degradation of cyclin-dependent kinase 4 (CDK4). Developed by Blueprint Medicines, the molecule is engineered to address the dose-limiting hematological toxicities, such as neutropenia, commonly associated with first-generation CDK4/6 inhibitors by selectively sparing CDK6. BLU-448 functions by facilitating the formation of a ternary complex between CDK4 and the cereblon (CRBN) E3 ubiquitin ligase, leading to the ubiquitination and subsequent proteasomal degradation of the CDK4 protein. In preclinical models of HR+/HER2- breast cancer, BLU-448 has demonstrated robust anti-tumor activity, characterized by sustained inhibition of retinoblastoma protein (RB) phosphorylation, G1 cell cycle arrest, and suppression of E2F-mediated gene transcription.