Article abstract
Nature Chemical Biology 4, 691 - 699 (2008)
Published online: 12 October 2008 | doi:10.1038/nchembio.117
Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases
Beth Apsel1, Jimmy A Blair2, Beatriz Gonzalez3,6, Tamim M Nazif4, Morri E Feldman1, Brian Aizenstein5, Randy Hoffman5, Roger L Williams3, Kevan M Shokat2,4 & Zachary A Knight4,6
Abstract
The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes.
- Program in Chemistry and Chemical Biology, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, USA.
- Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, USA.
- MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
- Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, USA.
- Invitrogen Corporation, 501 Charmany Drive, Madison, Wisconsin 53719, USA.
- Present addresses: Instituto de Química-Física Rocasolano (CSIC), Serrano 119, 28006 Madrid, Spain (B.G.) and The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA (Z.A.K.).
Correspondence to: Kevan M Shokat2,4 e-mail: shokat@cmp.ucsf.edu
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