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A Highly Selective and Potent PTP-MEG2 Inhibitor with Therapeutic Potential for Type 2 Diabetes
journal contribution
posted on 2012-10-31, 00:00 authored by Sheng Zhang, Sijiu Liu, Rongya Tao, Dan Wei, Lan Chen, Weihua Shen, Zhi-Hong Yu, Lina Wang, David
R. Jones, Xiaocheng C. Dong, Zhong-Yin ZhangProtein tyrosine phosphatases (PTPs) constitute a large
family
of signaling enzymes that control the cellular levels of protein tyrosine
phosphorylation. A detailed understanding of PTP functions in normal
physiology and in pathogenic conditions has been hampered by the absence
of PTP-specific, cell-permeable small-molecule agents. We present
a stepwise focused library approach that transforms a weak and general
non-hydrolyzable pTyr mimetic (F2Pmp, phosphonodifluoromethyl
phenylalanine) into a highly potent and selective inhibitor of PTP-MEG2,
an antagonist of hepatic insulin signaling. The crystal structures
of the PTP-MEG2-inhibitor complexes provide direct evidence that potent
and selective PTP inhibitors can be obtained by introducing molecular
diversity into the F2Pmp scaffold to engage both the active
site and unique nearby peripheral binding pockets. Importantly, the
PTP-MEG2 inhibitor possesses highly efficacious cellular activity
and is capable of augmenting insulin signaling and improving insulin
sensitivity and glucose homeostasis in diet-induced obese mice. The
results indicate that F2Pmp can be converted into highly
potent and selective PTP inhibitory agents with excellent in vivo efficacy. Given the general nature of the approach,
this strategy should be applicable to other members of the PTP superfamily.
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Keywords
agentType 2 DiabetesProtein tyrosine phosphatasescrystal structuresPTP superfamilyPTP functionsprotein tyrosine phosphorylationlibrary approachPTP inhibitorshepatic insulinvivo efficacyglucose homeostasisinsulin sensitivityF 2PmpF 2Pmp phosphonodifluoromethyl phenylalanineF 2Pmp scaffoldbinding pockets
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