2. Academic Validation
  3. Discovery of a novel series of potent and orally bioavailable phosphoinositide 3-kinase γ inhibitors

Discovery of a novel series of potent and orally bioavailable phosphoinositide 3-kinase γ inhibitors

  • J Med Chem. 2012 Jun 14;55(11):5467-82. doi: 10.1021/jm300403a.
James W Leahy 1,  Chris A Buhr,  Henry W B Johnson,  Byung Gyu Kim,  Taegon Baik,  Jonah Cannoy,  Timothy P Forsyth,  Joon Won Jeong,  Matthew S Lee,  Sunghoon Ma,  Kevin Noson,  Longcheng Wang,  Matthew Williams,  John M Nuss,  Eric Brooks,  Paul Foster,  Leanne Goon,  Nathan Heald,  Charles Holst,  Christopher Jaeger,  Scott Lam,  Julie Lougheed,  Lam Nguyen,  Arthur Plonowski,  Joanne Song,  Thomas Stout,  Xiang Wu,  Michael F Yakes,  Peiwen Yu,  Wentao Zhang,  Peter Lamb,  Olivia Raeber
Affiliations

Affiliation

  • 1 Department of Drug Discovery, Exelixis, 169 Harbor Way, South San Francisco, California 94083, United States.
PMID: 22548342 DOI: 10.1021/jm300403a
Abstract

The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these Enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kγ to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3Kγ revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability.

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