Development of single and mixed isoform selectivity PI3Kδ inhibitors by targeting Asn836 of PI3Kδ

Michelle S. Miller, Simon J. Mountford, Jo-Anne Pinson, Zhaohua Zheng, Marco Künzli, Vanit Patel, Simon J. Hogg, Jake Shortt, Ian G. Jennings, Philip E. Thompson

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A series of PI3Kδ inhibitors derived from the pan-PI3K inhibitor ZSTK474 was prepared that target a non-conserved region of the catalytic site. Dependent upon the substituents present, these analogues show different levels of isoform selectivity and sensitivity to the mutation N836D in PI3Kδ. As a marker of ‘on-target’ activity and permeability, a selection of the most potent PI3Kδ inhibitors were shown to inhibit pAkt production in the Nawalma Burkitt lymphoma cell line.

Original languageEnglish
Pages (from-to)4790-4794
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number19
DOIs
Publication statusPublished - 1 Oct 2016

Keywords

  • Isoform selectivity
  • Leukemia
  • Lymphoma
  • PI3 kinase inhibitor

Cite this

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title = "Development of single and mixed isoform selectivity PI3Kδ inhibitors by targeting Asn836 of PI3Kδ",
abstract = "A series of PI3Kδ inhibitors derived from the pan-PI3K inhibitor ZSTK474 was prepared that target a non-conserved region of the catalytic site. Dependent upon the substituents present, these analogues show different levels of isoform selectivity and sensitivity to the mutation N836D in PI3Kδ. As a marker of ‘on-target’ activity and permeability, a selection of the most potent PI3Kδ inhibitors were shown to inhibit pAkt production in the Nawalma Burkitt lymphoma cell line.",
keywords = "Isoform selectivity, Leukemia, Lymphoma, PI3 kinase inhibitor",
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journal = "Bioorganic and Medicinal Chemistry Letters",
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}

Development of single and mixed isoform selectivity PI3Kδ inhibitors by targeting Asn836 of PI3Kδ. / Miller, Michelle S.; Mountford, Simon J.; Pinson, Jo-Anne; Zheng, Zhaohua; Künzli, Marco; Patel, Vanit; Hogg, Simon J.; Shortt, Jake; Jennings, Ian G.; Thompson, Philip E.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 19, 01.10.2016, p. 4790-4794.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Development of single and mixed isoform selectivity PI3Kδ inhibitors by targeting Asn836 of PI3Kδ

AU - Miller, Michelle S.

AU - Mountford, Simon J.

AU - Pinson, Jo-Anne

AU - Zheng, Zhaohua

AU - Künzli, Marco

AU - Patel, Vanit

AU - Hogg, Simon J.

AU - Shortt, Jake

AU - Jennings, Ian G.

AU - Thompson, Philip E.

PY - 2016/10/1

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N2 - A series of PI3Kδ inhibitors derived from the pan-PI3K inhibitor ZSTK474 was prepared that target a non-conserved region of the catalytic site. Dependent upon the substituents present, these analogues show different levels of isoform selectivity and sensitivity to the mutation N836D in PI3Kδ. As a marker of ‘on-target’ activity and permeability, a selection of the most potent PI3Kδ inhibitors were shown to inhibit pAkt production in the Nawalma Burkitt lymphoma cell line.

AB - A series of PI3Kδ inhibitors derived from the pan-PI3K inhibitor ZSTK474 was prepared that target a non-conserved region of the catalytic site. Dependent upon the substituents present, these analogues show different levels of isoform selectivity and sensitivity to the mutation N836D in PI3Kδ. As a marker of ‘on-target’ activity and permeability, a selection of the most potent PI3Kδ inhibitors were shown to inhibit pAkt production in the Nawalma Burkitt lymphoma cell line.

KW - Isoform selectivity

KW - Leukemia

KW - Lymphoma

KW - PI3 kinase inhibitor

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