Steinmetzer Torsten, Schweinitz Andrea, Stürzebecher Anne, Dönnecke Daniel, Uhland Kerstin, Schuster Oliver, Steinmetzer Peter, Müller Friedemann, Friedrich Rainer, Than Manuel E, Bode Wolfram, Stürzebecher Jörg
Curacyte Chemistry GmbH, Winzerlaer Strasse 2, D-07745 Jena, Germany.
J Med Chem. 2006 Jul 13;49(14):4116-26. doi: 10.1021/jm051272l.
Matriptase is an epithelium-derived type II transmembrane serine protease and has been implicated in the activation of substrates such as pro-HGF/SF and pro-uPA, which are likely involved in tumor progression and metastasis. Through screening, we have identified bis-basic secondary amides of sulfonylated 3-amidinophenylalanine as matriptase inhibitors. X-ray analyses of analogues 8 and 31 in complex with matriptase revealed that these inhibitors occupy, in addition to part of the previously described S4-binding site, the cleft formed by the molecular surface and the unique 60 loop of matriptase. Therefore, optimization of the inhibitors included the incorporation of appropriate sulfonyl substituents that could improve binding of these inhibitors into both characteristic matriptase subsites. The most potent derivatives inhibit matriptase highly selective with K(i) values below 5 nM. Molecular modeling revealed that their improved affinity results from interaction with the S4 site of matriptase. Analogues 8 and 59 were studied in an orthotopic xenograft mouse model of prostate cancer. Compared to control, both inhibitors reduced tumor growth, as well as tumor dissemination.
Matriptase是一种上皮来源的II型跨膜丝氨酸蛋白酶，与前HGF/SF和前尿激酶型纤溶酶原激活剂等底物的激活有关，这些底物可能参与肿瘤进展和转移。通过筛选，我们鉴定出磺酰化3-脒基苯丙氨酸的双碱性仲酰胺作为Matriptase抑制剂。与Matriptase复合的类似物8和31的X射线分析表明，这些抑制剂除占据先前描述的S4结合位点的一部分外，还占据由Matriptase分子表面和独特的60环形成的裂隙。因此，抑制剂的优化包括引入合适的磺酰基取代基，以改善这些抑制剂与Matriptase两个特征性亚位点的结合。最有效的衍生物对Matriptase具有高度选择性抑制作用，其K(i)值低于5 nM。分子模拟表明，它们亲和力的提高源于与Matriptase的S4位点的相互作用。在前列腺癌原位异种移植小鼠模型中研究了类似物8和59。与对照组相比，两种抑制剂均能减少肿瘤生长以及肿瘤扩散。
