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

journal contribution
posted on 2008-01-01, 00:00 authored by M Frazzetto, Cenk SuphiogluCenk Suphioglu, J Zhu, O Schmidt-Kittler, I Jennings, S Cranmer, S Jackson, K Kinzler, B Vogelstein, P Thompson
The last few years have seen the identification of numerous small molecules that selectively inhibit 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 α 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.

History

Journal

Biochemical journal

Volume

414

Issue

3

Pagination

383 - 390

Publisher

Portland Press Ltd

Location

London, England

ISSN

0264-6021

eISSN

1470-8728

Language

eng

Publication classification

C1 Refereed article in a scholarly journal

Copyright notice

2008, The Authors