Selective protein tyrosine phosphatase 1B inhibitors: targeting the second phosphotyrosine binding site with non-carboxylic acid-containing ligands.
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.
Liu
Gang
G
Metabolic Disease Research and Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6098, USA. gang.liu@abbott.com
Xin
Zhili
Z
Liang
Heng
H
Abad-Zapatero
Cele
C
Hajduk
Philip J
PJ
Janowick
David A
DA
Szczepankiewicz
Bruce G
BG
Pei
Zhonghua
Z
Hutchins
Charles W
CW
Ballaron
Stephen J
SJ
Stashko
Michael A
MA
Lubben
Thomas H
TH
Berg
Cathy E
CE
Rondinone
Cristina M
CM
Trevillyan
James M
JM
Jirousek
Michael R
MR
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
D004791:Enzyme Inhibitors; D008024:Ligands; D012459:Salicylates; D019000:Phosphotyrosine; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases