title: Structure-based optimization of pyrazolo-pyrimidine and -pyridine inhibitors of PI3-kinase.
abstract: Starting from HTS hit 1a, X-ray co-crystallization and molecular modeling were used to design potent and selective inhibitors of PI3-kinase. Bioavailablity in this series was improved through careful modulation of physicochemical properties. Compound 12 displayed in vivo knockdown of PI3K pharmacodynamic markers such as pAKT, pPRAS40, and pS6RP in a PC3 prostate cancer xenograft model.
authors.affiliation: Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA. stevents@gene.com
authors.forename: Steven T
authors.initials: ST
authors.lastname: Staben
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffron
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sutherlin
authors.forename: Seema R
authors.initials: SR
authors.lastname: Bhat
authors.forename: Georgette M
authors.initials: GM
authors.lastname: Castanedo
authors.forename: Irina S
authors.initials: IS
authors.lastname: Chuckowree
authors.forename: Jenna
authors.initials: J
authors.lastname: Dotson
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Folkes
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.forename: Leslie
authors.initials: L
authors.lastname: Lee
authors.forename: John
authors.initials: J
authors.lastname: Lesnick
authors.forename: Cristina
authors.initials: C
authors.lastname: Lewis
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Murray
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Alan G
authors.initials: AG
authors.lastname: Olivero
authors.forename: Emile
authors.initials: E
authors.lastname: Plise
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.forename: Wei Wei
authors.initials: WW
authors.lastname: Prior
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Lionel
authors.initials: L
authors.lastname: Rouge
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.forename: Nan Chi
authors.initials: NC
authors.lastname: Wan
authors.forename: Shumei
authors.initials: S
authors.lastname: Wang
authors.forename: Christian
authors.initials: C
authors.lastname: Weismann
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Bing-Yan
authors.initials: BY
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; C023666:pyridine