2. Academic Validation
  3. Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kα

Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kα

  • J Med Chem. 2013 Feb 14;56(3):712-21. doi: 10.1021/jm3008745.
Mariana Nacht 1,  Lixin Qiao,  Michael P Sheets,  Thia St Martin,  Matthew Labenski,  Hormoz Mazdiyasni,  Russell Karp,  Zhendong Zhu,  Prasoon Chaturvedi,  Deepa Bhavsar,  Deqiang Niu,  William Westlin,  Russell C Petter,  Aravind Prasad Medikonda,  Juswinder Singh
Affiliations

Affiliation

  • 1 Celgene Avilomics Research, 45 Wiggins Avenue, Bedford, Massachusetts 01730, USA. mnacht@celgene.com
PMID: 23360348 DOI: 10.1021/jm3008745
Abstract

PI3Kα has been identified as an oncogene in human tumors. By use of rational drug design, a targeted covalent inhibitor 3 (CNX-1351) was created that potently and specifically inhibits PI3Kα. We demonstrate, using mass spectrometry and X-ray crystallography, that the selective inhibitor covalently modifies PI3Kα on cysteine 862 (C862), an amino acid unique to the α isoform, and that PI3Kβ, -γ, and -δ are not covalently modified. 3 is able to potently (EC(50) < 100 nM) and specifically inhibit signaling in PI3Kα-dependent Cancer cell lines, and this leads to a potent antiproliferative effect (GI(50) < 100 nM). A covalent probe, 8 (CNX-1220), which selectively bonds to PI3Kα, was used to investigate the duration of occupancy of 3 with PI3Kα in vivo. This is the first report of a PI3Kα-selective inhibitor, and these data demonstrate the biological impact of selectively targeting PI3Kα.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16596
    99.88%, PI3Kα抑制剂
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