Dissecting isoform selectivity of P13K inhibitors: The role of non-conserved residues in the catalytic pocket

Mark Frazzetto, Cenk Suphioglu, Jiuxiang Zhu, Oleg Schmidt-Kittler, Ian G. Jennings, Susan L. Cranmer, Shaun P. Jackson, Kenneth W. Kinzler, Bert Vogelstein, Philip E. Thompson

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


The last few years have seen the identification of numerous small molecules that selectively inbibit specific class I isoforms of PI3K (phosphoinositide 3-kinase), yet little has been revealed about the molecular basis for the observed selectivities. Using site-directed mutagenesis, we have investigated one of the areas postulated as being critical to the observed selectivity. The residues Thr886 and Lys890 of the PI3Kγ isoform project towards the ATP-binding pocket at the entrance to the catalytic site, but are not conserved. We have made reciprocal mutations between those residues in the β isoform (Glu858 and Asp862) and those in the ct isoform (His855 and Gln859) and evaluated the potency of a range of reported PI3K inhibitors. The results show that the potencies of β-selective inhibitors TGX221 and TGX286 are unaffected by this change. In contrast, close analogues of these compounds, particularly the α- isoform-selective compound (III), are markedly influenced by the point mutations. The collected data suggests two distinct binding poses for these inhibitor classes, one of which is associated with potent PI3Kβ activity and is not associated with the mutated residues, and a second that, in accord with earlier hypotheses, does involve this pair of non-conserved amino acids at the catalytic site entrance and contributes to the α-isoform-selectivity of the compounds studied.

Original languageEnglish (US)
Pages (from-to)383-390
Number of pages8
JournalBiochemical Journal
Issue number3
StatePublished - Sep 15 2008


  • 3-kinase (P13K)
  • ATP-binding pocket
  • Phosphoinositide
  • Site-directed mutagenesis
  • Small-molecule inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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