MS28

MS28 is a first-in-class bridged proteolysis-targeting chimera (PROTAC) designed to degrade the undruggable protein cyclin D1. Developed by researchers at the Icahn School of Medicine at Mount Sinai, the University of North Carolina at Chapel Hill, and Cullgen, MS28 utilizes a novel "bridged PROTAC" strategy. Because cyclin D1 lacks a direct small-molecule binder, MS28 is designed to bind to its binding partner, cyclin-dependent kinase 4 and 6 (CDK4/6), using a palbociclib-derived moiety. This recruits the CDK4/6-cyclin D1 complex into close proximity with the von Hippel-Lindau (VHL) E3 ubiquitin ligase, leading to the preferential polyubiquitination and subsequent proteasomal degradation of cyclin D1. MS28 has demonstrated potent antiproliferative activity in preclinical models of non-small cell lung cancer (NSCLC), melanoma, and breast cancer, including triple-negative breast cancer (TNBC) cell lines that are typically insensitive to standard CDK4/6 inhibitors and degraders.