Discovery of pyrrolopyrimidine inhibitors of Akt.
The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.
Blake
James F
JF
Array BioPharma Inc, 3200 Walnut Street, Boulder, CO 80301, USA. jblake@arraybiopharma.com
Kallan
Nicholas C
NC
Xiao
Dengming
D
Xu
Rui
R
Bencsik
Josef R
JR
Skelton
Nicholas J
NJ
Spencer
Keith L
KL
Mitchell
Ian S
IS
Woessner
Richard D
RD
Gloor
Susan L
SL
Risom
Tyler
T
Gross
Stefan D
SD
Martinson
Matthew
M
Morales
Tony H
TH
Vigers
Guy P A
GP
Brandhuber
Barbara J
BJ
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C527741:pyrrolopyrimidine; D051057:Proto-Oncogene Proteins c-akt