Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 1: design, synthesis and biological activity.
HTS screening identified 1 with micromolar inhibitory activity against PDK1. Optimization of 1 afforded 4i (BX-517) which has single-digit nanomolar activity against PDK1 and excellent selectivity against PKA.
Islam
Imadul
I
Berlex Biosciences, 2600 Hilltop Dr. Richmond, CA 94804, USA.
Bryant
Judi
J
Chou
Yuo-Ling
YL
Kochanny
Monica J
MJ
Lee
Wheeseong
W
Phillips
Gary B
GB
Yu
Hongyi
H
Adler
Marc
M
Whitlow
Marc
M
Ho
Elena
E
Lentz
Dao
D
Polokoff
Mark A
MA
Subramanyam
Babu
B
Wu
James M
JM
Zhu
Daguang
D
Feldman
Richard I
RI
Arnaiz
Damian O
DO
D064413:3-Phosphoinositide-Dependent Protein Kinases; D015195:Drug Design; D007211:Indoles / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D007211:Indoles; D047428:Protein Kinase Inhibitors; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases