Identifying new allosteric sites on PTP1B using fragment-based tether scanning

Recorded On: 02/07/2018

Due to its role in regulating insulin receptor kinase, protein-tyrosine phosphatase 1B (PTP1B) has been a long sought after drug target for the treatment of diabetes and other metabolic disorders. Unfortunately, due to the high homology between PTP family members and the charged nature of substrate mimics, developing selective and cell-permeable active site inhibitors of PTP1B has proven notoriously difficult. For this reason, there has been great interest in developing compounds that allosterically modulate PTP1B activity. Towards this goal, we have been applying a disulfide-tethering fragment-based approach to identify and characterize new binding and allosteric sites on PTP1B. Here we report our progress to date, and show that this “Tether Scanning” approach has allowed us to identify new binding sites on PTP1B, as well as new disulfide fragments that modulate PTP1B activity. 

Zachary Hill

University of California, San Francisco

Zachary is currently a postdoctoral fellow in Jim Wells' lab at UCSF, where he works on the development of chemical biology approaches to identify and study new bioactive small molecules. Prior to coming to UCSF, Zachary completed his PhD in Organic Chemistry with Dustin Maly at the University of Washington, where he worked on the development of bivalent kinase inhibitors. During his postdoc, Zachary has been fortunate enough to be supported by a fellowship from the Helen Hay Whitney Foundation, as well as a K99 Transition award from the NIH-NCI. In the next year, Zachary hopes to transition to an independent position where he will continue applying ligand-based approaches to study biological systems. 

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