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Structure-Based Design and Discovery of Protein Tyrosine Phosphatase Inhibitors Incorporating Novel Isothiazolidinone Heterocyclic Phosphotyrosine Mimetics

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journal contribution
posted on 20.10.2005, 00:00 by Andrew P. Combs, Eddy W. Yue, Michael Bower, Paul J. Ala, Brian Wayland, Brent Douty, Amy Takvorian, Padmaja Polam, Zelda Wasserman, Wenyu Zhu, Matthew L. Crawley, James Pruitt, Richard Sparks, Brian Glass, Dilip Modi, Erin McLaughlin, Lori Bostrom, Mei Li, Laurine Galya, Karl Blom, Milton Hillman, Lucie Gonneville, Brian G. Reid, Min Wei, Mary Becker-Pasha, Ronald Klabe, Reid Huber, Yanlong Li, Gregory Hollis, Timothy C. Burn, Richard Wynn, Phillip Liu, Brian Metcalf
Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.