Goswami Rajeev, Mukherjee Subhendu, Ghadiyaram Chakshusmathi, Wohlfahrt Gerd, Sistla Ramesh K, Nagaraj Jwala, Satyam Leena K, Subbarao Krishnaprasad, Palakurthy Rajendra K, Gopinath Sreevalsam, Krishnamurthy Narasimha R, Ikonen Tarja, Moilanen Anu, Subramanya Hosahalli S, Kallio Pekka, Ramachandra Murali
Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
Orion Corporation, Orionintie 1, FIN-02101 Espoo, Finland.
Bioorg Med Chem. 2014 Jun 15;22(12):3187-203. doi: 10.1016/j.bmc.2014.04.013. Epub 2014 Apr 18.
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.
胃蛋白酶（matriptase）是一种与癌症侵袭和转移相关的丝氨酸蛋白酶。胃蛋白酶的表达在人类癌症中经常失调，据报道胃蛋白酶可激活潜在生长因子，如肝细胞生长因子/分散因子，以及蛋白酶，如尿激酶型纤溶酶原激活剂，这表明胃蛋白酶抑制剂在癌症治疗中可能具有治疗潜力。在此，我们报道了一种基于结构的方法，该方法导致发现了以苯为中心核、具有1,3,5三取代模式的选择性强效胃蛋白酶抑制剂。一种强效类似物与胃蛋白酶复合物的X射线晶体学研究表明，在S1口袋中存在强氢键和盐桥相互作用，以及P2/P4环己基与色氨酸215侧链之间的强CH-π接触。环己基上的侧链胺与谷氨酰胺175侧链的额外相互作用导致胃蛋白酶抑制作用以及对其他相关丝氨酸蛋白酶的选择性有显著改善。化合物15和26在皮下DU-145前列腺癌小鼠模型中显示出肿瘤生长抑制作用。这些化合物可用作进一步探索胃蛋白酶作为药物靶点的生物学特性的工具。
