Discovery of MD-265: A Potent MDM2 Degrader That Achieves Complete Tumor Regression and Improves Long-Term Survival of Mice with Leukemia

MDM2 has been pursued as an attractive therapeutic target
for human
cancers. Herein, we describe our discovery of MD-265 as a promising
PROTAC MDM2 degrader and extensive in vitro and in vivo evaluations of its therapeutic potential and mechanism
of action. MD-265 effectively depleted MDM2 protein in cancer cells
at concentrations as low as 1 nM, leading to strong activation of
p53 in cancer cells carrying wild-type p53. It selectively inhibited
the growth of wild-type p53 leukemia cell lines and showed no activity
in mutated p53 lines. MD-265 achieved persistent tumor regression
in a leukemia xenograft model without causing any signs of toxicity
and dramatically improved survival of mice in a disseminated leukemia
model even with a weekly administration. MD-265 displayed an excellent
intravenous PK profile in mice, rats, and dogs. MD-265 is a promising
MDM2 degrader for advanced preclinical development for the treatment
of human cancers.