title: Conformationally-restricted cyclic sulfones as potent and selective mTOR kinase inhibitors.
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.
authors: Pfizer Global Research and Development, Chemistry Department, La Jolla, CA 92120, USA. Liu_Kang_Zhi_Kevin@Lilly.com
authors: Kevin K-C
authors: KK
authors: Liu
authors: Simon
authors: S
authors: Bailey
authors: Dac M
authors: DM
authors: Dinh
authors: Hieu
authors: H
authors: Lam
authors: Chunze
authors: C
authors: Li
authors: Peter A
authors: PA
authors: Wells
authors: Min-Jean
authors: MJ
authors: Yin
authors: Aihua
authors: A
authors: Zou
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D006207:Half-Life; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017434:Protein Structure, Tertiary; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013450:Sulfones; D058570:TOR Serine-Threonine Kinases; C576339:PF-05139962