Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration.
Fragment-based screening identified 7-azaindole as a protein kinase B inhibitor scaffold. Fragment elaboration using iterative crystallography of inhibitor-PKA-PKB chimera complexes efficiently guided improvements in the potency and selectivity of the compounds, resulting in the identification of nanomolar 6-(piperidin-1-yl)purine, 4-(piperidin-1-yl)-7-azaindole, and 4-(piperidin-1-yl)pyrrolo[2,3- d]pyrimidine inhibitors of PKBbeta with antiproliferative activity and showing pathway inhibition in cells. A divergence in the binding mode was seen between 4-aminomethylpiperidine and 4-aminopiperidine containing molecules. Selectivity for PKB vs PKA was observed with 4-aminopiperidine derivatives, and the most PKB-selective inhibitor (30-fold) showed significantly different bound conformations between PKA and PKA-PKB chimera.
Caldwell
John J
JJ
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, U.K.
Davies
Thomas G
TG
Donald
Alastair
A
McHardy
Tatiana
T
Rowlands
Martin G
MG
Aherne
G Wynne
GW
Hunter
Lisa K
LK
Taylor
Kevin
K
Ruddle
Ruth
R
Raynaud
Florence I
FI
Verdonk
Marcel
M
Workman
Paul
P
Garrett
Michelle D
MD
Collins
Ian
I
D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid / Q000379:methods; D018360:Crystallography, X-Ray; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
C561680:4-(4-chlorobenzyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidin-4-amine; D004791:Enzyme Inhibitors; D008024:Ligands; D011743:Pyrimidines; D011758:Pyrroles; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases