Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy.
Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor. Inhibition of PTP1B is expected to improve insulin action, and the design of small molecule PTP1B inhibitors to treat type II diabetes has received considerable attention. In this work, NMR-based screening identified a nonselective competitive inhibitor of PTP1B. A second site ligand was also identified by NMR-based screening and then linked to the catalytic site ligand by rational design. X-ray data confirmed that the inhibitor bound with the catalytic site in the native, "open" conformation. The final compound displayed excellent potency and good selectivity over many other phosphatases. The modular approach to drug design described in this work should be applicable for the design of potent and selective inhibitors of other therapeutically relevant protein tyrosine phosphatases.
Szczepankiewicz
Bruce G
BG
Metabolic Disease Research, Global Pharmaceutical Research and Development Organization, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. bruce.szczepankiewicz@abbott.com
Liu
Gang
G
Hajduk
Philip J
PJ
Abad-Zapatero
Cele
C
Pei
Zhonghua
Z
Xin
Zhili
Z
Lubben
Thomas H
TH
Trevillyan
James M
JM
Stashko
Michael A
MA
Ballaron
Stephen J
SJ
Liang
Heng
H
Huang
Flora
F
Hutchins
Charles W
CW
Fesik
Stephen W
SW
Jirousek
Michael R
MR
D000595:Amino Acid Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D002384:Catalysis; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D010072:Oxamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D011487:Protein Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D008024:Ligands; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D010072:Oxamic Acid