title: Structure-guided discovery of 1,3,5 tri-substituted benzenes as potent and selective matriptase inhibitors exhibiting in vivo antitumor efficacy.
abstract: Matriptase is a serine protease implicated in cancer invasion and metastasis. Expression of matriptase is frequently dysregulated in human cancers and matriptase has been reported to activate latent growth factors such as hepatocyte growth factor/scatter factor, and proteases such as urokinase plasminogen activator suggesting that matriptase inhibitors could have therapeutic potential in treatment of cancer. Here we report a structure-based approach which led to the discovery of selective and potent matriptase inhibitors with benzene as central core having 1,3,5 tri-substitution pattern. X-ray crystallography of one of the potent analogs in complex with matriptase revealed strong hydrogen bonding and salt-bridge interactions in the S1 pocket, as well as strong CH-π contacts between the P2/P4 cyclohexyl and Trp215 side-chain. An additional interaction of the pendant amine at cyclohexyl with Gln175 side-chain results in substantial improvement in matriptase inhibition and selectivity against other related serine proteases. Compounds 15 and 26 showed tumor growth inhibition in a subcutaneous DU-145 prostate cancer mouse model. These compounds could be useful as tools to further explore the biology of matriptase as a drug target.
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: 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: 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: Ramesh K
authors.initials: RK
authors.lastname: Sistla
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: 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: 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: Orion Corporation, Orionintie 1, FIN-02101 Espoo, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Ikonen
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: Hosahalli S
authors.initials: HS
authors.lastname: Subramanya
authors.affiliation: Orion Corporation, Tengströminkatu 8, FIN-20101 Turku, Finland.
authors.forename: Pekka
authors.initials: P
authors.lastname: Kallio
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: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D001554:Benzene / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects*; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000600996:(1r,4r)-4-amino-N-(3,5-bis(4-carbamimidoylphenoxy)phenyl)cyclohexanecarboxamide; D000970:Antineoplastic Agents; D001549:Benzamides; D003510:Cyclohexanes; C000600997:N-(4-aminocyclohexyl)-3,5-bis(4-carbamimidoylphenoxy)benzamide; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C485595:matriptase; D001554:Benzene
keywords: Amidine; Cancer; Crystallography; In vivo activity; Matriptase; Molecular docking