Discovery of Selective Matriptase and Hepsin Serine Protease Inhibitors: Useful Chemical Tools for Cancer Cell Biology
| Autor: | Shishir M. Pant, Vishnu C. Damalanka, James W. Janetka, Juha Klefström, Florencia La Greca, Zhenfu Han, Anthony J. O’Donoghue, Charles S. Craik, Tommy Kim, Partha Karmakar, Jonathan D.M. Helander |
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| Rok vydání: | 2018 |
| Předmět: |
Proteases
Cell signaling C-Met Serine Proteinase Inhibitors Hepsin medicine.medical_treatment Drug Evaluation Preclinical 01 natural sciences Substrate Specificity 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Cell Line Tumor Drug Discovery medicine Structure–activity relationship Humans Matriptase 030304 developmental biology 0303 health sciences Protease Binding Sites biology Serine Endopeptidases Dipeptides 3. Good health 0104 chemical sciences Protein Structure Tertiary Molecular Docking Simulation 010404 medicinal & biomolecular chemistry chemistry Tumor progression Cancer research biology.protein Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 62(2) |
| ISSN: | 1520-4804 |
| Popis: | Matriptase and hepsin belong to the family of type II transmembrane serine proteases (TTSPs). Increased activity of these and the plasma protease, hepatocyte growth factor activator (HGFA), is associated with unregulated cell signaling and tumor progression through increased MET and RON kinase signaling pathways. These proteases are highly expressed in multiple solid tumors and hematological malignancies. Herein, we detail the synthesis and structure-activity relationships (SAR) of a dipeptide library bearing Arg α-ketobenozothiazole (kbt) warheads as novel inhibitors of HGFA, matriptase, and hepsin. We elucidated the substrate specificity for HGFA using positional scanning of substrate combinatorial libraries (PS-SCL), which was used to discover selective inhibitors of matriptase and hepsin. Using these selective inhibitors, we have clarified the specific role of hepsin in maintaining epithelial cell membrane integrity, known to be lost in breast cancer progression. These selective compounds are useful as chemical biology tools and for future drug discovery efforts. |
| Databáze: | OpenAIRE |
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