title: Discovery of O-(3-carbamimidoylphenyl)-l-serine amides as matriptase inhibitors using a fragment-linking approach.
abstract: 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.
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: 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: Chakshusmathi
authors.initials: C
authors.lastname: Ghadiyaram
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: Leena K
authors.initials: LK
authors.lastname: Satyam
authors.affiliation: Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Krishnaprasad
authors.initials: K
authors.lastname: Subbarao
authors.affiliation: Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
authors.forename: Sreevalsam
authors.initials: S
authors.lastname: Gopinath
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: Hosahalli S
authors.initials: HS
authors.lastname: Subramanya
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: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006207:Half-Life; D007700:Kinetics; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D011485:Protein Binding; D012694:Serine / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D015842:Serine Proteinase Inhibitors; D012694:Serine; D012697:Serine Endopeptidases; C485595:matriptase
keywords: Anti-tumor; Crystallography; Fragment-linking approach; Matriptase; Molecular docking