Department of Chemistry, McGill University, 801 Sherbrooke St. W., Montréal, Québec, H3A 0B8, Canada.
Department of Chemistry, McGill University, 801 Sherbrooke St. W., Montréal, Québec, H3A 0B8, Canada.
Eur J Med Chem. 2022 Oct 5;240:114543. doi: 10.1016/j.ejmech.2022.114543. Epub 2022 Jun 17.
We have previously described several different chemical series of bicyclic prolyl oligopeptidase (POP) inhibitors as probes for neurodegenerative diseases that demonstrated nanomolar activity in vitro and submicromolar activity in cellulo. The more recent implication of POP in cancer, together with homologous fibroblast activation protein α (FAP), implicated in tumor growth, led us to consider developing POP/FAP dual inhibitors as a promising strategy for the development of cancer therapeutics. At this stage, we thought to evaluate the requirements for selectivity of inhibitors for POP over FAP and to evaluate molecular platforms that would enable the development of selective POP and dual POP/FAP inhibitors. We report herein docking-guided design of a new bicyclic scaffold and synthesis of both covalent and non-covalent bicyclic inhibitors. Biological evaluation of first-of-their-kind [4.3.0] bicyclic compounds confirmed that reactive groups, or covalent warheads, are required for inhibitor activity. This work ultimately led to one scaffold yielding new POP-selective inhibitors and a dual inhibitor equipotent to the only drug targeting FAP and POP that ever reached clinical trials.
我们之前已经描述了几种不同的双环脯氨酰寡肽酶 (POP) 抑制剂的化学系列，这些抑制剂被用作神经退行性疾病的探针，在体外具有纳摩尔级的活性，在细胞内具有亚微米级的活性。最近 POP 在癌症中的作用以及同源的成纤维细胞激活蛋白α（FAP）的作用，与肿瘤生长有关，这促使我们考虑开发 POP/FAP 双重抑制剂作为癌症治疗的一种有前途的策略。在现阶段，我们认为需要评估抑制剂对 POP 相对于 FAP 的选择性，并评估能够开发选择性 POP 和双重 POP/FAP 抑制剂的分子平台。我们在此报告了一种新的双环支架的基于对接的设计和合成，以及共价和非共价双环抑制剂。首例 [4.3.0] 双环化合物的生物学评估证实，反应性基团或共价弹头对于抑制剂的活性是必需的。这项工作最终产生了一种支架，该支架产生了新的 POP 选择性抑制剂，以及一种与唯一一种靶向 FAP 和 POP 的药物等效的双重抑制剂，该药物曾进入临床试验。
