Structure-guided discovery of 2-aryl/pyridin-2-yl-1H-indole derivatives as potent and selective hepsin inhibitors
| Autor: | Karthikeyan Narasingapuram Arumugam, Jwala Nagaraj, DS Samiulla, Murali Ramachandra, Rajendra K. Palakurthy, Rajeev Goswami, Olli Törmäkangas, Anirudha Lakshminarasimhan, Narasimha Rao Krishnamurthy, Gerd Wohlfahrt, Anu Moilanen, Subhendu Mukherjee, Mahaboobi Jaleel, Anita R. Chacko |
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| Rok vydání: | 2015 |
| Předmět: |
Indoles
Serine Proteinase Inhibitors Pyridines Stereochemistry Hepsin Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Biochemistry Amidine Mice chemistry.chemical_compound Cell Movement Cyclohexanes Cell Line Tumor Drug Discovery Animals Humans Neoplasm Invasiveness Molecular Biology Serine protease Indole test biology Chemistry Aryl Serine Endopeptidases Organic Chemistry Transmembrane protein Molecular Docking Simulation Cell culture Microsomes Liver biology.protein Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25:5309-5314 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2015.09.042 |
| Popis: | Hepsin, a type II transmembrane serine protease, is upregulated in prostate cancer and known to be involved in the progression of metastasis. Here we report a structure-guided approach, which resulted in the discovery of 2-aryl/pyridin-2-yl-1H-indole derivatives as potent and selective inhibitors of hepsin. Potent and selective inhibition of hepsin by compound 8 is likely due to interactions of the amidine group at the S1 site with the cyclohexyl ring from the 2-aryl group projecting towards the S1' site and the tert-hydroxyl group interacting with His57 side-chain as revealed by X-ray crystallography. Compounds 8 and 10, showed Ki of 0.1 μM for hepsin, and exhibited inhibition of invasion and migration of hepsin-overexpressing cell line. Compounds described here could serve as useful tool reagents to investigate the role of hepsin as a potential therapeutic target in cancer. |
| Databáze: | OpenAIRE |
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