Discovery of\nMD-265: A Potent MDM2 Degrader That Achieves\nComplete Tumor Regression and Improves Long-Term Survival of Mice\nwith Leukemia

MDM2 has been pursued as an attractive therapeutic target\nfor human\ncancers. Herein, we describe our discovery of MD-265 as a promising\nPROTAC MDM2 degrader and extensive <i>in vitro</i> and <i>in vivo</i> evaluations of its therapeutic potential and mechanism\nof action. MD-265 effectively depleted MDM2 protein in cancer cells\nat concentrations as low as 1 nM, leading to strong activation of\np53 in cancer cells carrying wild-type p53. It selectively inhibited\nthe growth of wild-type p53 leukemia cell lines and showed no activity\nin mutated p53 lines. MD-265 achieved persistent tumor regression\nin a leukemia xenograft model without causing any signs of toxicity\nand dramatically improved survival of mice in a disseminated leukemia\nmodel even with a weekly administration. MD-265 displayed an excellent\nintravenous PK profile in mice, rats, and dogs. MD-265 is a promising\nMDM2 degrader for advanced preclinical development for the treatment\nof human cancers.