Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression

Human murine double
minute 2 (MDM2) protein is a primary endogenous cellular inhibitor
of the tumor suppressor p53 and has been pursued as an attractive
cancer therapeutic target. Several potent, nonpeptide, small-molecule
inhibitors of MDM2 are currently in clinical development. In this
paper, we report our design, synthesis, and evaluation of small-molecule
MDM2 degraders based on the proteolysis targeting chimera (PROTAC)
concept. The most promising compound (MD-224) effectively induces
rapid degradation of MDM2 at concentrations <1 nM in human leukemia
cells. It achieves an IC50 value of 1.5 nM in inhibition
of growth of RS4;11 cells and also low nanomolar IC50 values
in a panel of leukemia cell lines. MD-224 achieves complete and durable
tumor regression in vivo in the RS4;11 xenograft tumor model in mice
at well-tolerated dose schedules. MD-224 is thus a highly potent and
efficacious MDM2 degrader and warrants extensive evaluations as a
new class of anticancer agent.