Discovery of O-(3-carbamimidoylphenyl)-l-serine amides as matriptase inhibitors using a fragment-linking approach
| Autor: | Rajeev Goswami, Subhendu Mukherjee, Gerd Wohlfahrt, Jwala Nagaraj, Krishnaprasad Subbarao, Chakshusmathi Ghadiyaram, Narasimha Rao Krishnamurthy, Leena Khare Satyam, Sreevalsam Gopinath, Hosahalli Subramanya, Murali Ramachandra |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Proteases Serine Proteinase Inhibitors Clinical Biochemistry Pharmaceutical Science Inflammation Crystallography X-Ray Biochemistry Mice Structure-Activity Relationship chemistry.chemical_compound Catalytic Domain Drug Discovery Hydrolase Serine medicine Animals Matriptase Molecular Biology Serine protease Binding Sites biology Serine Endopeptidases Organic Chemistry Cancer medicine.disease Amides Molecular Docking Simulation Kinetics chemistry biology.protein Molecular Medicine Hepatocyte growth factor Growth inhibition medicine.symptom Half-Life Protein Binding medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25:616-620 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2014.12.008 |
| Popis: | Matriptase is a cell-surface trypsin-like serine protease of epithelial origin, which cleaves and activates proteins including hepatocyte growth factor/scatter factor and proteases such as uPA, which are involved in the progression of various cancers. Here we report a fragment-linking approach, which led to the discovery of O-(3-carbamimidoylphenyl)-l-serine amides as potent matriptase inhibitors. The co-crystal structure of one of the potent inhibitors, 6 in complex with matriptase catalytic domain validated the working hypothesis guiding the development of this congeneric series and revealed the structural basis for matriptase inhibition. Replacement of a naphthyl group in 6 with 2,4,6-tri-isopropyl phenyl resulted in 10 with improved matriptase inhibition, which exhibited significant primary tumor growth inhibition in a mouse model of prostate cancer. Compounds such as 10, identified using a fragment-linking approach, can be explored further to understand the role of matriptase as a drug target in cancer and inflammation. |
| Databáze: | OpenAIRE |
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