TY - JOUR
T1 - L-aminoacyl-triazine derivatives are isoform-selective PI3KB inhibitors that target nonconserved Asp862 of PI3KB
AU - Pinson, Jo-Anne
AU - Zheng, Zhaohua
AU - Miller, Michelle Susan
AU - Chalmers, David Kenneth
AU - Jennings, Ian
AU - Thompson, Philip
PY - 2013
Y1 - 2013
N2 - A series of aminoacyl-triazine derivatives based upon the pan-PI3K inhibitor ZSTK474 were identified as potent and isoform-selective inhibitors of PI3K beta. The compounds showed selectivity based upon stereochemistry with L-amino acyl derivatives preferring PI3K beta, while their D-congeners favored PI3K delta. The mechanistic basis of this inhibition was studied using site-directed mutants. One Asp residue, D862, was identified as a critical participant in binding to the PI3K beta-selective inhibitors, distinguishing this class from other reported PI3K beta-selective inhibitors. The compounds show strong inhibition of cellular Akt phosphorylation and growth of PTEN-deficient MD-MBA-468 cells.
AB - A series of aminoacyl-triazine derivatives based upon the pan-PI3K inhibitor ZSTK474 were identified as potent and isoform-selective inhibitors of PI3K beta. The compounds showed selectivity based upon stereochemistry with L-amino acyl derivatives preferring PI3K beta, while their D-congeners favored PI3K delta. The mechanistic basis of this inhibition was studied using site-directed mutants. One Asp residue, D862, was identified as a critical participant in binding to the PI3K beta-selective inhibitors, distinguishing this class from other reported PI3K beta-selective inhibitors. The compounds show strong inhibition of cellular Akt phosphorylation and growth of PTEN-deficient MD-MBA-468 cells.
UR - http://pubs.acs.org/doi/pdf/10.1021/ml300336j
U2 - 10.1021/ml300336j
DO - 10.1021/ml300336j
M3 - Article
SN - 1948-5875
VL - 4
SP - 206
EP - 210
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 2
ER -