Fisher Jed F, Mobashery Shahriar
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556-5670, USA.
Cancer Metastasis Rev. 2006 Mar;25(1):115-36. doi: 10.1007/s10555-006-7894-9.
The search for an MMP inhibitor with anticancer efficacy is a nearly three-decade endeavor. This inhibitor is yet to be found. The reasons for this failure include shortcomings in the chemistry of these compounds (including broad MMP sub-type selectivity, metabolic lability, and toxicity) as well as the emerging, and arguably extraordinary, complexity of MMP cell (and cancer) biology. Together these suggest that the successful anticancer inhibitor must possess MMP selectivity against the MMP subtype whose involvement is critical, yet highly temporally (with respect to metastatic progression) and mechanistically (with respect to matrix degradation) regulated. This review summarizes the progression of chemical structure and mechanistic thinking toward these objectives, with emphasis on the disappointment, the perseverance, and the resilient optimism that such an inhibitor is there to be discovered.
寻找具有抗癌功效的基质金属蛋白酶（MMP）抑制剂是一项历经近三十年的努力。然而，这种抑制剂尚未被找到。失败的原因包括这些化合物在化学性质上的缺陷（包括对MMP亚型的广泛选择性、代谢不稳定性和毒性），以及MMP细胞（和癌症）生物学新出现的、可以说是极其复杂的情况。综合来看，这表明成功的抗癌抑制剂必须对关键的MMP亚型具有MMP选择性，而且在时间上（相对于转移进展）和机制上（相对于基质降解）受到高度调控。本综述总结了为实现这些目标在化学结构和机制方面的思考进展，重点讲述了失望、坚持以及对发现此类抑制剂的坚定乐观态度。
