| Literature DB >> 26985323 |
Stéphane L Bogen1, Weidong Pan1, Craig R Gibeau2, Brian R Lahue2, Yao Ma2, Latha G Nair1, Elise Seigel1, Gerald W Shipps2, Yuan Tian2, Yaolin Wang3, Yinghui Lin3, Ming Liu3, Suxing Liu3, Asra Mirza3, Xiaoying Wang3, Philip Lipari3, Cynthia Seidel-Dugan3, Daniel J Hicklin3, W Robert Bishop3, Diane Rindgen4, Amin Nomeir4, Winifred Prosise5, Paul Reichert5, Giovanna Scapin5, Corey Strickland5, Ronald J Doll1.
Abstract
A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23-ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described.Entities:
Keywords: HDM2; cancer; p53; protein−protein interaction
Year: 2016 PMID： 26985323 PMCID： PMC4789661 DOI： 10.1021/acsmedchemlett.5b00472
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345