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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Targeting the disordered C terminus of PTP1B with an allosteric inhibitor
Navasona Krishnan1, Dorothy Koveal2, Daniel H Miller3
1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
Abstract:
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.
Insights
Researchers discovered a new way to inhibit PTP1B, a key protein in breast cancer. The small molecule MSI-1436 targets a disordered segment, offering a promising therapeutic strategy for breast cancer treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for diabetes and obesity.
- PTP1B plays a critical role in HER2 signaling, promoting breast tumorigenesis.
- Developing PTP1B inhibitors has been challenging due to the active site's chemical properties.
Purpose of the Study:
- To define a novel mechanism of allosteric inhibition targeting the C-terminal, noncatalytic segment of PTP1B.
- To identify small-molecule binding sites within PTP1B, including its intrinsically disordered segment.
- To validate PTP1B inhibition as a therapeutic strategy for breast cancer.
Main Methods:
- Determined the ensemble structure of PTP1B, including its intrinsically disordered C-terminal segment.
- Identified a binding site for the small-molecule inhibitor MSI-1436 within the disordered segment.
- Demonstrated cooperative binding of MSI-1436 to two distinct sites, leading to PTP1B inactivation.
Main Results:
- MSI-1436 binds to a novel allosteric site within the disordered C-terminal segment of PTP1B.
- Cooperative binding of MSI-1436 to two sites induces a locked, inactive state of PTP1B.
- MSI-1436 effectively antagonized HER2 signaling, inhibited tumor growth in xenografts, and reduced metastasis in a mouse model.
Conclusions:
- Allosteric inhibition targeting the disordered C-terminal segment represents a new therapeutic strategy for PTP1B.
- MSI-1436 demonstrates the potential of targeting intrinsically disordered protein segments for drug development.
- Inhibiting PTP1B is a validated therapeutic approach for breast cancer, particularly in HER2-driven tumors.
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