title: Isothiazolidinone heterocycles as inhibitors of protein tyrosine phosphatases: synthesis and structure-activity relationships of a peptide scaffold.
abstract: The structure-based design and discovery of the isothiazolidinone (IZD) heterocycle as a mimic of phosphotyrosine (pTyr) has led to the identification of novel IZD-containing inhibitors of protein tyrosine phosphatase 1B (PTP1B). The structure-activity relationships (SARs) of peptidic IZD-containing inhibitors of PTP1B are described along with a novel synthesis of the aryl-IZD fragments via a Suzuki coupling. The SAR revealed the saturated IZD heterocycle (42) is the most potent heterocyclic pTyr mimetic compared to the unsaturated IZD (25), the thiadiazolidinone (TDZ) (38), and the regioisomeric unsaturated IZD (31). The X-ray crystal structures of 11c and 25 complexed with PTP1B were solved and revealed nearly identical binding interactions in the active site. Ab initio calculations effectively explain the strong binding of the (S)-IZD due to the preorganized binding of the IZD in its low energy conformation.
authors.affiliation: Incyte Corporation, Discovery Chemistry, Experimental Station, Route 141, Henry Clay Road, Wilmington, DE 19880, USA. eddyyue@incyte.com
authors.forename: Eddy W
authors.initials: EW
authors.lastname: Yue
authors.forename: Brian
authors.initials: B
authors.lastname: Wayland
authors.forename: Brent
authors.initials: B
authors.lastname: Douty
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Crawley
authors.forename: Eric
authors.initials: E
authors.lastname: McLaughlin
authors.forename: Amy
authors.initials: A
authors.lastname: Takvorian
authors.forename: Zelda
authors.initials: Z
authors.lastname: Wasserman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bower
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Li
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Ala
authors.forename: Lucie
authors.initials: L
authors.lastname: Gonneville
authors.forename: Richard
authors.initials: R
authors.lastname: Wynn
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Burn
authors.forename: Phillip C C
authors.initials: PC
authors.lastname: Liu
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Combs
mesh_terms: D004926:Escherichia coli; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D013844:Thiazoles; C516607:PTPN1 protein, human; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases