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Ref Type Journal Article
PMID (24845231)
Authors Krishnan N, Koveal D, Miller DH, Xue B, Akshinthala SD, Kragelj J, Jensen MR, Gauss CM, Page R, Blackledge M, Muthuswamy SK, Peti W, Tonks NK
Title Targeting the disordered C terminus of PTP1B with an allosteric inhibitor.
Journal Vol Issue Date Pages Journal Short Title
Nature chemical biology 10 7 2014 Jul 558-66 Nat Chem Biol
URL
Abstract Text PTP1B, a validated therapeutic target for diabetes and obesity, has a critical positive role in HER2 signaling in breast tumorigenesis. Efforts to develop therapeutic inhibitors of PTP1B have been frustrated by the chemical properties of the active site. We define a new mechanism of allosteric inhibition that targets the C-terminal, noncatalytic segment of PTP1B. We present what is to our knowledge the first ensemble structure of PTP1B containing this intrinsically disordered segment, within which we identified a binding site for the small-molecule inhibitor MSI-1436. We demonstrate binding to a second site close to the catalytic domain, with cooperative effects between the two sites locking PTP1B in an inactive state. MSI-1436 antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer. This new approach to inhibition of PTP1B emphasizes the potential of disordered segments of proteins as specific binding sites for therapeutic small molecules.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Trodusquemine Trodusquemine 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
Trodusquemine MSI-1436|MSI1436|Aminosterol-1436 Trodusquemine (MSI-1436) is a small molecule allosteric inhibitor of PTP1B, which results in reduced tumor growth (PMID: 24845231).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References