title: Structure-guided discovery of 2-aryl/pyridin-2-yl-1H-indole derivatives as potent and selective hepsin inhibitors.
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-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.
authors.affiliation: Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Goswami
authors.affiliation: Orion Corporation, Orionintie 1, FIN-02101 Espoo, Finland.
authors.forename: Gerd
authors.initials: G
authors.lastname: Wohlfahrt
authors.affiliation: Orion Corporation, Tengströminkatu 8, FIN-20101 Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Törmäkangas
authors.affiliation: Orion Corporation, Tengströminkatu 8, FIN-20101 Turku, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Moilanen
authors.affiliation: Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Anirudha
authors.initials: A
authors.lastname: Lakshminarasimhan
authors.affiliation: Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Jwala
authors.initials: J
authors.lastname: Nagaraj
authors.affiliation: Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Karthikeyan N
authors.initials: KN
authors.lastname: Arumugam
authors.affiliation: Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Subhendu
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Anita R
authors.initials: AR
authors.lastname: Chacko
authors.affiliation: Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Narasimha R
authors.initials: NR
authors.lastname: Krishnamurthy
authors.affiliation: Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Mahaboobi
authors.initials: M
authors.lastname: Jaleel
authors.affiliation: Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Palakurthy
authors.affiliation: Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Dodheri S
authors.initials: DS
authors.lastname: Samiulla
authors.affiliation: Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India. Electronic address: murali_r@aurigene.com.
authors.forename: Murali
authors.initials: M
authors.lastname: Ramachandra
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D009361:Neoplasm Invasiveness; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C000608578:2-(6-(1-fluoro-cyclohexyl)-pyridin-2-yl)-1H-indole-5-carboxamidine; C000608577:2-(6-(1-hydroxy-cyclohexyl)-pyridin-2-yl)-1H-indole-5-carboxamidine; D000970:Antineoplastic Agents; D003510:Cyclohexanes; D007211:Indoles; D011725:Pyridines; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C055645:hepsin
keywords: Cancer; Crystallography; Hepsin; Indole; Molecular docking