title: Structure-based optimization of morpholino-triazines as PI3K and mTOR inhibitors.
abstract: A virtual screen of our in-house database using various fingerprint techniques returned several triazine hits which were found to be mTOR inhibitors with a slight selectivity over PI3Kα. Using structure-guided lead optimization the inhibitory activity towards mTOR and PI3Kα was increased to the low nanomolar range. Exploiting shape differences in the binding-site allowed for the design of mTOR selective inhibitors. Focus on ligand efficiency ensured the inhibitors retained a low molecular weight and desirable drug-like properties.
authors.affiliation: S∗BIO Pte Ltd, 1 Science Park Road, #05-09 The Capricorn, Singapore Science Park II, Singapore 117528, Singapore. anders@colours.dk
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.forename: Meredith
authors.initials: M
authors.lastname: Williams
authors.forename: Harish Mysore
authors.initials: HM
authors.lastname: Nagaraj
authors.forename: Anthony D
authors.initials: AD
authors.lastname: William
authors.forename: Haishan
authors.initials: H
authors.lastname: Wang
authors.forename: Chang Kai
authors.initials: CK
authors.lastname: Soh
authors.forename: Zheng Chang
authors.initials: ZC
authors.lastname: Xiong
authors.forename: Brian
authors.initials: B
authors.lastname: Dymock
mesh_terms: D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D014227:Triazines; D058570:TOR Serine-Threonine Kinases