Nature Biotechnology
23, 329 - 336 (2005)
Published online: 13 February 2005; | doi:10.1038/nbt1068
A small molecule−kinase interaction map for clinical kinase inhibitorsMiles A Fabian1, 3, William H Biggs III1, 3, Daniel K Treiber1, 3, Corey E Atteridge1, Mihai D Azimioara1, 2, Michael G Benedetti1, 3, Todd A Carter1, Pietro Ciceri1, Philip T Edeen1, Mark Floyd1, Julia M Ford1, Margaret Galvin1, Jay L Gerlach1, Robert M Grotzfeld1, Sanna Herrgard1, Darren E Insko1, Michael A Insko1, Andiliy G Lai1, Jean-Michel Lélias1, Shamal A Mehta1, Zdravko V Milanov1, Anne Marie Velasco1, Lisa M Wodicka1, Hitesh K Patel1, Patrick P Zarrinkar1
& David J Lockhart11
Ambit Biosciences, 4215 Sorrento Valley Blvd., San Diego, California 92121, USA. 2
Present addresses: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Dr., San Diego, California 92121, USA (M.D.A.), Buck Institute, 8001 Redwood Blvd., Novato, California 94945, USA (M.G.B.), Seattle Biomedical Research Institute, 307 Westlake Ave. N., Ste. 500, Seattle, Washington 98109, USA (J.L.G.) and Metabasis Therapeutics, 9390 Towne Centre Dr., San Diego, California 92121, USA (M.A.I.). 3
These authors contributed equally to this work.
Correspondence should be addressed to David J Lockhart dlockhart@ambitbio.com or Patrick P Zarrinkar pzarrinkar@ambitbio.comKinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LCK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.
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