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

doi:10.1021/ml300336j

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

Medicinal Chemistry

Research output: Contribution to journal › Article › Research › peer-review

26 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	206 - 210
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	4
Issue number	2
DOIs	https://doi.org/10.1021/ml300336j
Publication status	Published - 2013

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10.1021/ml300336j

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Pinson, J-A., Zheng, Z., Miller, M. S., Chalmers, D. K., Jennings, I., & Thompson, P. (2013). L-aminoacyl-triazine derivatives are isoform-selective PI3KB inhibitors that target nonconserved Asp862 of PI3KB. ACS Medicinal Chemistry Letters, 4(2), 206 - 210. https://doi.org/10.1021/ml300336j

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abstract = "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.",

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L-aminoacyl-triazine derivatives are isoform-selective PI3KB inhibitors that target nonconserved Asp862 of PI3KB. / Pinson, Jo-Anne; Zheng, Zhaohua; Miller, Michelle Susan; Chalmers, David Kenneth ; Jennings, Ian ; Thompson, Philip.

In: ACS Medicinal Chemistry Letters, Vol. 4, No. 2, 2013, p. 206 - 210.

Research output: Contribution to journal › Article › Research › peer-review

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AU - Pinson, Jo-Anne

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AU - Jennings, Ian

AU - Thompson, Philip

PY - 2013

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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.

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