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.
Array BioPharma Inc., Boulder, CO 80301, USA. jbencsik@arraybiopharma.com
Josef R
JR
Bencsik
Dengming
D
Xiao
James F
JF
Blake
Nicholas C
NC
Kallan
Ian S
IS
Mitchell
Keith L
KL
Spencer
Rui
R
Xu
Susan L
SL
Gloor
Matthew
M
Martinson
Tyler
T
Risom
Richard D
RD
Woessner
Faith
F
Dizon
Wen-I
WI
Wu
Guy P A
GP
Vigers
Barbara J
BJ
Brandhuber
Nicholas J
NJ
Skelton
Wei Wei
WW
Prior
Lesley J
LJ
Murray
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