Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
J Med Chem. 2009 Dec 24;52(24):7970-3. doi: 10.1021/jm901400z.
We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a K(i) of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.
我们在此报告了强效和口服活性的 MDM2-p53 相互作用小分子抑制剂的设计。化合物 5 与 MDM2 的结合 Ki 值为 0.6 nM，在低至 40 nM 的浓度下即可激活 p53，并在野生型 p53 的肿瘤细胞中比在突变/缺失 p53 的肿瘤细胞中更有效地选择性抑制细胞生长。化合物 5 具有良好的口服生物利用度，能有效地抑制 SJSA-1 异种移植模型中的肿瘤生长。
