Discovery of novel inhibitor of human leukocyte common antigen-related phosphatase.
Human leukocyte common antigen-related phosphatase (LAR) may play a role in type 2 diabetes and cancer, and in the development of the nervous system, and it may be an attractive target for the treatment of diabetes and cancer. We identified eight hits from the random screening of LAR D1 with a high-throughput screening assay. Further validation of the eight hits showed that the meD insertion was associated with inhibition of LAR D1D2 and LAR D1Q. These data suggest that the inserted meD peptide influences the interaction of the enzyme and inhibitor, which is consistent with the kinetic catalysis constants of the substrate pNPP. Our data showed that Hit 1, the first published novel inhibitor of LAR, is a competitive inhibitor with a K(i) of 330 nM that displays obvious selectivity for LAR and mouse PTPsigma, but not for other protein tyrosine phosphatases.
Yang
Xiaoning
X
East China Normal University, Academy of Life Science, Shanghai 200062, P. R. China.
Li
Jingya
J
Zhou
Yueyang
Y
Shen
Qiang
Q
Chen
Jiwu
J
Li
Jia
J
D000818:Animals; D004926:Escherichia coli; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013379:Substrate Specificity
D007328:Insulin; D011956:Receptors, Cell Surface; D012717:Sesquiterpenes; C516841:PTPRA protein, human; D017027:Protein Tyrosine Phosphatases; C516843:Ptpra protein, mouse; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4