Conformationally-restricted cyclic sulfones as potent and selective mTOR kinase inhibitors

Kevin K-C Liu; Simon Bailey; Dac M Dinh; Hieu Lam; Chunze Li; Peter A Wells; Min-Jean Yin; Aihua Zou

doi:10.1016/j.bmcl.2012.05.104

Conformationally-restricted cyclic sulfones as potent and selective mTOR kinase inhibitors

Bioorg Med Chem Lett. 2012 Aug 1;22(15):5114-7. doi: 10.1016/j.bmcl.2012.05.104. Epub 2012 Jun 6.

Authors

Kevin K-C Liu¹, Simon Bailey, Dac M Dinh, Hieu Lam, Chunze Li, Peter A Wells, Min-Jean Yin, Aihua Zou

Affiliation

¹ Pfizer Global Research and Development, Chemistry Department, La Jolla, CA 92120, USA. Liu_Kang_Zhi_Kevin@Lilly.com

PMID: 22765900
DOI: 10.1016/j.bmcl.2012.05.104

Abstract

Novel conformationally-restricted mTOR kinase inhibitors with cyclic sulfone scaffold were designed. Synthesis and structure-activity relationship (SAR) studies are described with emphasis on optimization of the mTOR potency and selectivity against class I PI3Kα kinase. PF-05139962 was identified with excellent mTOR biochemical inhibition, cellular potency, kinase selectivity and in vitro ADME properties.

MeSH terms

Animals
Binding Sites
Computer Simulation
Half-Life
Humans
Microsomes, Liver / metabolism
Morpholines / chemical synthesis
Morpholines / chemistry*
Morpholines / pharmacokinetics
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Structure, Tertiary
Rats
Structure-Activity Relationship
Sulfones / chemical synthesis
Sulfones / chemistry*
Sulfones / pharmacokinetics
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / metabolism

Substances

Morpholines
PF-05139962
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Sulfones
TOR Serine-Threonine Kinases