Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
J Med Chem. 2021 Apr 8;64(7):4071-4088. doi: 10.1021/acs.jmedchem.0c02188. Epub 2021 Mar 24.
Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent and inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.
小分子抑制鼠双微体 2（MDM2）-p53 蛋白-蛋白相互作用已被证明可重新激活 p53 并抑制肿瘤生长。在这里，我们描述了基于合理的、结构导向的新型异吲哚啉酮基 MDM2 抑制剂的设计。MDM2 X 射线晶体学、量子力学配体设计和代谢产物鉴定都有助于发现强效的 MDM2-p53 相互作用抑制剂，代表性化合物在 SJSA-1 骨肉瘤异种移植模型中，每日口服一次即可诱导细胞停滞。
