Potent and Orally Active Small-Molecule Inhibitors of the MDM2−p53 Interaction
Shanghai Yu(University of Michigan), Dongguang Qin(University of Michigan), Sanjeev Shangary(University of Michigan), Jianyong Chen(University of Michigan), Guoping Wang(University of Michigan), Ke Ding(University of Michigan), Donna McEachern(University of Michigan), Su Qiu(University of Michigan), Zaneta Nikolovska‐Coleska(University of Michigan), Rebecca S. Miller(University of Michigan), Sanmao Kang(Lindenwood University), Dajun Yang(State Key Laboratory of Oncology in South China), Shaomeng Wang(University of Michigan)
Cited by 177Open Access
Abstract
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.
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