Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors.
Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg.
Bencsik
Josef R
JR
Array BioPharma Inc., Boulder, CO 80301, USA. jbencsik@arraybiopharma.com
Xiao
Dengming
D
Blake
James F
JF
Kallan
Nicholas C
NC
Mitchell
Ian S
IS
Spencer
Keith L
KL
Xu
Rui
R
Gloor
Susan L
SL
Martinson
Matthew
M
Risom
Tyler
T
Woessner
Richard D
RD
Dizon
Faith
F
Wu
Wen-I
WI
Vigers
Guy P A
GP
Brandhuber
Barbara J
BJ
Skelton
Nicholas J
NJ
Prior
Wei Wei
WW
Murray
Lesley J
LJ
D000818:Animals; D001665:Binding Sites; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D047368:Tumor Burden / Q000187:drug effects
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051057:Proto-Oncogene Proteins c-akt