TY - JOUR
T1 - Potent and highly selective inhibitors of the protein tyrosine phosphatase 1B
AU - Taing, Meng
AU - Keng, Yen Fang
AU - Shen, Kui
AU - Wu, Li
AU - Lawrence, David S.
AU - Zhang, Zhong Yin
PY - 1999/3/23
Y1 - 1999/3/23
N2 - Several protein tyrosine phosphatases (PTPases) have been implicated as regulatory agents in the insulin-stimulated signal transduction pathway, including PTP1B, PTPα, and LAR. Furthermore, since all three enzymes are suggested to serve as negative regulators of insulin signaling, one or more may play a pivotal role in the pathogenesis of insulin resistance. We report herein the acquisition of highly selective PTP1B-targeted inhibitors. We recently demonstrated that PTP1B contains two proximal aromatic phosphate binding sites [Puius, Y. A., Zhao, Y., Sullivan, M., Lawrence, D. S., Almo S. C., and Zhang, Z. Y. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 13420-5], and we have now employed this structural feature to design and synthesize an array of bis(aryldifluorophosphonates). Not only do the lead compounds serve as potent inhibitors of PTP1B but, in addition, several exhibit selectivities for PTP1B versus PTPα, LAR, and VHR that are greater than 2 orders in magnitude.
AB - Several protein tyrosine phosphatases (PTPases) have been implicated as regulatory agents in the insulin-stimulated signal transduction pathway, including PTP1B, PTPα, and LAR. Furthermore, since all three enzymes are suggested to serve as negative regulators of insulin signaling, one or more may play a pivotal role in the pathogenesis of insulin resistance. We report herein the acquisition of highly selective PTP1B-targeted inhibitors. We recently demonstrated that PTP1B contains two proximal aromatic phosphate binding sites [Puius, Y. A., Zhao, Y., Sullivan, M., Lawrence, D. S., Almo S. C., and Zhang, Z. Y. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 13420-5], and we have now employed this structural feature to design and synthesize an array of bis(aryldifluorophosphonates). Not only do the lead compounds serve as potent inhibitors of PTP1B but, in addition, several exhibit selectivities for PTP1B versus PTPα, LAR, and VHR that are greater than 2 orders in magnitude.
UR - http://www.scopus.com/inward/record.url?scp=0033596855&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033596855&partnerID=8YFLogxK
U2 - 10.1021/bi9813781
DO - 10.1021/bi9813781
M3 - Article
C2 - 10090769
AN - SCOPUS:0033596855
SN - 0006-2960
VL - 38
SP - 3793
EP - 3803
JO - Biochemistry®
JF - Biochemistry®
IS - 12
ER -