L-aminoacyl-triazine derivatives are isoform-selective PI3KB inhibitors that target nonconserved Asp862 of PI3KB

Jo-Anne Pinson, Zhaohua Zheng, Michelle Susan Miller, David Kenneth Chalmers, Ian Jennings, Philip Thompson

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26 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)206 - 210
Number of pages5
JournalACS Medicinal Chemistry Letters
Issue number2
Publication statusPublished - 2013

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