Structure-based optimization of pyrazolo-pyrimidine and -pyridine inhibitors of PI3-kinase.
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.
Staben
Steven T
ST
Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA. stevents@gene.com
Heffron
Timothy P
TP
Sutherlin
Daniel P
DP
Bhat
Seema R
SR
Castanedo
Georgette M
GM
Chuckowree
Irina S
IS
Dotson
Jenna
J
Folkes
Adrian J
AJ
Friedman
Lori S
LS
Lee
Leslie
L
Lesnick
John
J
Lewis
Cristina
C
Murray
Jeremy M
JM
Nonomiya
Jim
J
Olivero
Alan G
AG
Plise
Emile
E
Pang
Jodie
J
Prior
Wei Wei
WW
Salphati
Laurent
L
Rouge
Lionel
L
Sampath
Deepak
D
Tsui
Vickie
V
Wan
Nan Chi
NC
Wang
Shumei
S
Weismann
Christian
C
Wu
Ping
P
Zhu
Bing-Yan
BY
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
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; C023666:pyridine