title: Selective protein tyrosine phosphatase 1B inhibitors: targeting the second phosphotyrosine binding site with non-carboxylic acid-containing ligands.
abstract: Protein tyrosine phosphatase (PTPase) 1B (PTP1B) has been implicated as a key negative regulator of both insulin and leptin signaling cascades. We identified several salicylic acid-based ligands for the second phosphotyrosine binding site of PTP1B using a NMR-based screening. Structure-based linking with a catalytic site-directed oxalylarylaminobenzoic acid-based pharmacophore led to the identification of a novel series of potent PTP1B inhibitors exhibiting 6-fold selectivity over the highly homologous T-cell PTPase (TCPTP) and high selectivity over other phosphatases.
authors.affiliation: Metabolic Disease Research and Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6098, USA. gang.liu@abbott.com
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Zhili
authors.initials: Z
authors.lastname: Xin
authors.forename: Heng
authors.initials: H
authors.lastname: Liang
authors.forename: Cele
authors.initials: C
authors.lastname: Abad-Zapatero
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hajduk
authors.forename: David A
authors.initials: DA
authors.lastname: Janowick
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Szczepankiewicz
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
authors.forename: Charles W
authors.initials: CW
authors.lastname: Hutchins
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ballaron
authors.forename: Michael A
authors.initials: MA
authors.lastname: Stashko
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Lubben
authors.forename: Cathy E
authors.initials: CE
authors.lastname: Berg
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Rondinone
authors.forename: James M
authors.initials: JM
authors.lastname: Trevillyan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jirousek
mesh_terms: D020134:Catalytic Domain; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D019000:Phosphotyrosine / Q000737:chemistry*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012459:Salicylates / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D012459:Salicylates; D019000:Phosphotyrosine; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases