1618-52-6Relevant academic research and scientific papers
Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy
Szczepankiewicz, Bruce G.,Liu, Gang,Hajduk, Philip J.,Abad-Zapatero, Cele,Pei, Zhonghua,Xin, Zhili,Lubben, Thomas H.,Trevillyan, James M.,Stashko, Michael A.,Ballaron, Stephen J.,Liang, Heng,Huang, Flora,Hutchins, Charles W.,Fesik, Stephen W.,Jirousek, Michael R.
, p. 4087 - 4096 (2007/10/03)
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.
Discovery and structure-activity relationship of oxalylarylaminobenzoic acids as inhibitors of protein tyrosine phosphatase 1B
Liu, Gang,Szczepankiewicz, Bruce G.,Pei, Zhonghua,Janowick, David A.,Xin, Zhili,Hajduk, Philip J.,Abad-Zapatero, Cele,Liang, Heng,Hutchins, Charles W.,Fesik, Stephen W.,Ballaron, Steve J.,Stashko, Mike A.,Lubben, Tom,Mika, Amanda K.,Zinker, Bradley A.,Trevillyan, James M.,Jirousek, Michael R.
, p. 2093 - 2103 (2007/10/03)
Protein Tyrosine phosphatase 1B (PTP1B) has been implicated as a key negative regulator of both insulin and leptin signaling pathways. Using an NMR-based screening approach with 15N- and 13C-labeled PTP1B, we have identified 2,3-dimethylphenyloxalylaminobenzoic acid (1) as a general, reversible, and competitive PTPase inhibitor. Structure-based approach guided by X-ray crystallography facilitated the development of 1 into a novel series of potent and selective PTP1B inhibitors occupying both the catalytic site and a portion of the noncatalytic, second phosphotyrosine binding site. Interestingly, oral biovailability has been observed in rats for some compounds. Furthermore, we demonstrated in vivo plasma glucose lowering effects with compound 12d in ob/ob mice.
