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Abstract
Grant Number: 1R43DK063764-01 PI Name: MC DOWELL, ROBERT S. PI Email: rsm@sunesis.com PI Title: DIRECTOR Project Title: Bimodal PTP-1B Inhibitors using Tethering Technology Abstract: DESCRIPTION (provided by applicant): The long-term objective of this proposal is to apply a powerful "covalent tethering" technology to discover novel therapeutics for the treatment of type 2 diabetes. Protein tyrosine phosphatase-1B (PTP-1B) has emerged as a compelling target for treating diabetes, but it has been difficult to identify cell permeable, drug-like inhibitors of this important enzyme. Covalent tethering technology involves discovering drug-like fragments that bind to a target protein and assembling them into potent inhibitors. Cysteine mutations are introduced to target a site of interest and a collection of disulfide-containing fragments are screened to identify compounds that bind and form a disulfide bond. Compared to traditional screening, a greater chemical diversity is surveyed by identifying the individual components of binding and subsequently combining them into a common molecule. We propose to use covalent tethering and structure-based design to target two adjacent binding sites on PTP-1B. We will first identify pharmaceutically desirable phophotyrosine mimetics for the conserved active site and then identify fragments that bind to a unique, nearby site. These fragments will be merged into a bimodal inhibitor that combines potency and specificity to overcome problems observed with existing inhibitors. Covalent tethering is ideally suited to identifying such bimodal molecules.
Thesaurus Terms:
diabetes mellitus therapy, drug discovery /isolation, enzyme inhibitor, noninsulin dependent diabetes mellitus, protein tyrosine phosphatase
active site, binding site, biotherapeutic agent, cysteine, structural biology
X ray crystallography, mass spectrometry
Institution: SUNESIS PHARMACEUTICALS, INC. 341 OYSTER POINT BLVD SOUTH SAN FRANCISCO, CA 94080 Fiscal Year: 2003 Department: Project Start: 01-MAR-2003 Project End: 28-FEB-2005 ICD: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES IRG: ZRG1