Structure-guided discovery of 1,3,5 tri-substituted benzenes as potent and selective matriptase inhibitors exhibiting in vivo antitumor efficacy

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• 作者：Rajeev Goswami^a ; Subhendu Mukherjee^a ; Chakshusmathi Ghadiyaram^a ; Gerd Wohlfahrt^b ; Ramesh K. Sistla^a ; Jwala Nagaraj^a ; Leena K. Satyam^a ; Krishnaprasad Subbarao^a ; Rajendra K. Palakurthy^a ; Sreevalsam Gopinath^a ; Narasimha R. Krishnamurthy^a ; Tarja Ikonen^b ; Anu Moilanen^c ; Hosahalli S. Subramanya^a ; Pekka Kallio^c ; Murali Ramachandra^a ; ^{murali_r@aurigene.com" class="auth_mail}
• 关键词：Ac ; acetyl ; Boc ; tert-butoxycarbonyl ; DCM ; dichloromethane ; DIPEA ; di-iso-propylethylamine ; DMF ; N ; N-dimethylformamide ; DMAP ; 4-dimethylaminopyridine ; EDCI ; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ; EtOAc ; ethyl acetate ; EtOH ; ethanol ; Et2O ; diethyl ether ; HOBt ; 1-N-hydroxybenzotriazole ; Py ; pyridine ; SAR ; structure&ndash ; activity relationship ; HPLC ; high pressure liquid chromatography ; LCMS ; liquid chromatography&ndash ; mass spectrometry ; MeOH ; methanol ; mp ; melting point ; rt
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：15 June 2014
• 年：2014
• 卷：22
• 期：12
• 页码：3187-3203
• 全文大小：5535 K

文摘

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–蟺 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.