Structure-guided discovery of 2-aryl/pyridin-2-yl-1H-indole derivatives as potent and selective hepsin inhibitors. Issue 22 (15th November 2015)

• Record Type: Journal Article
• Authors: Goswami, Rajeev; Wohlfahrt, Gerd; Törmäkangas, Olli; Moilanen, Anu; Lakshminarasimhan, Anirudha; Nagaraj, Jwala; Arumugam, Karthikeyan N.; Mukherjee, Subhendu; Chacko, Anita R.; Krishnamurthy, Narasimha R.; Jaleel, Mahaboobi; Palakurthy, Rajendra K.; Samiulla, Dodheri S.; Ramachandra, Murali
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 22(2015)
• Page Start: 5309
• Page End: 5314
• Publication Date: 2015-11-15
• Subjects: Hepsin -- Indole -- Molecular docking -- Crystallography -- Cancer; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.09.042
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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-1 H -indole derivatives as potent and selective inhibitors of hepsin. Potent and selective inhibition of hepsin by compound8 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. Compounds8 and10, showed K i 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.