title: Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics.
abstract: 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.
authors.affiliation: Discovery Chemistry, Incyte Corporation, Experimental Station, E336/132A, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA. acombs@incyte.com
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Combs
authors.forename: Eddy W
authors.initials: EW
authors.lastname: Yue
authors.forename: Michael
authors.initials: M
authors.lastname: Bower
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Ala
authors.forename: Brian
authors.initials: B
authors.lastname: Wayland
authors.forename: Brent
authors.initials: B
authors.lastname: Douty
authors.forename: Amy
authors.initials: A
authors.lastname: Takvorian
authors.forename: Padmaja
authors.initials: P
authors.lastname: Polam
authors.forename: Zelda
authors.initials: Z
authors.lastname: Wasserman
authors.forename: Wenyu
authors.initials: W
authors.lastname: Zhu
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Crawley
authors.forename: James
authors.initials: J
authors.lastname: Pruitt
authors.forename: Richard
authors.initials: R
authors.lastname: Sparks
authors.forename: Brian
authors.initials: B
authors.lastname: Glass
authors.forename: Dilip
authors.initials: D
authors.lastname: Modi
authors.forename: Erin
authors.initials: E
authors.lastname: McLaughlin
authors.forename: Lori
authors.initials: L
authors.lastname: Bostrom
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.forename: Laurine
authors.initials: L
authors.lastname: Galya
authors.forename: Karl
authors.initials: K
authors.lastname: Blom
authors.forename: Milton
authors.initials: M
authors.lastname: Hillman
authors.forename: Lucie
authors.initials: L
authors.lastname: Gonneville
authors.forename: Brian G
authors.initials: BG
authors.lastname: Reid
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Mary
authors.initials: M
authors.lastname: Becker-Pasha
authors.forename: Ronald
authors.initials: R
authors.lastname: Klabe
authors.forename: Reid
authors.initials: R
authors.lastname: Huber
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Li
authors.forename: Gregory
authors.initials: G
authors.lastname: Hollis
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Burn
authors.forename: Richard
authors.initials: R
authors.lastname: Wynn
authors.forename: Phillip
authors.initials: P
authors.lastname: Liu
authors.forename: Brian
authors.initials: B
authors.lastname: Metcalf
mesh_terms: D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D008958:Models, Molecular; D018716:Molecular Mimicry; D019000:Phosphotyrosine / Q000737:chemistry*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D004151:Dipeptides; D013844:Thiazoles; D019000:Phosphotyrosine; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases