COMP 332

Successful structure-based design of novel protein tyrosine phosphatase inhibitors

Michael J. Bower, mbower@incyte.com¹, Andrew P. Combs, acombs@incyte.com¹, Eddy W. Yue¹, Paul J. Ala², Brian Wayland¹, Brent Douty¹, Amy Takvorian¹, Padmaja Polam¹, Zelda Wasserman¹, Wenyu Zhu¹, Matthew Crawley¹, James Pruitt¹, Richard Sparks¹, Brian Glass¹, Dilip Modi¹, Erin McLaughlin¹, Lori Bostrom³, Mei Li¹, Laurine Galya¹, Karl Blom¹, Milton Hillman², Lucie Gonneville², Brian G. Reid², Min Wei², Mary Becker-Pasha², Ronald Klabe², Reid Huber², Yanlong Li², Gregory Hollis², Timothy C. Burn², Richard Wynn², Phillip Liu², and Brian Metcalf¹. (1) Discovery Chemistry, Incyte Corporation, Experimental Station, 141 & Henry Clay Rd, Wilmington, DE 19880-0500, (2) Discovery Biology, Incyte Corporation, Experimental Station, 141 & Henry Clay Rd, Wilmington, DE 19880-0500, (3) Incyte Corporation, Experimental Station, 141 & Henry Clay Rd, Wilmington, DE 19880-0500

Through structure-based combination of geometric features from diverse classes of inhibitors crystallized in complex with protein tyrosine phosphatase 1B (PTP1B), we were able to design a novel heterocyclic phosphotyrosine mimic. This designed heterocycle is the basis for a class of extremely potent, competitive, and reversible inhibitors of PTP1B. Crystal structures of PTP1B in complex with these inhibitors show that the phosphotyrosine mimic binds in the active site of the enzyme exactly as designed. This work represents the potential power of structure-based design approaches in targets for which there is a fair amount of structural data available.

General Oral - Drug Discovery
8:00 AM-11:55 AM, Thursday, 30 March 2006 Georgia World Congress Center -- B306, Oral

Division of Computers in Chemistry

The 231st ACS National Meeting, Atlanta, GA, March 26-30, 2006