CRM1非共价抑制剂的发现、设计、合成与抗白血病的机制研究

CRM1 is an essential exportin in cells, which is overexpressed in a large variety of tumors and associated with drug resistance. The inhibition of CRM1 controls the cellular localization of many cargoes including tumor suppressors, cell cycle regulators, and apoptosis-related proteins, and thus it probably would be more effective against cancer than targeting a single pathway. All reported CRM1 inhibitors are covalent inhibitors. In our preliminary study, we identified several iridium complexes and Mefloquine as CRM1 inhibitors (IC50 = 1.6 - 22.1 μm), which also had potent anti-cancer activities against leukemia K562 cells (IC50 = 0.26 – 9.80 μm). These compounds did not contain Michael receptors and were structurally different from all reported CRM1 inhibitors. We plan to use computer-aided drug design technology to optimize the structures of the iridium complexes and mefloquine as CRM1 inhibitors, use GST Pull-down assays and MTT assays to screen compounds, use X-ray crystallography to reveal the binding modes of iridium complexes and mefloquine analogues, study their anti-leukemia mechanisms, and study their efficacy against leukemia and toxicity based on animal models. We hope to provide more information for the development of non-covalent CRM1 inhibitors as potential anti-leukemia therapeutics.

CRM1是重要的出核运输蛋白，在多种肿瘤中高表达并与肿瘤的耐药密切相关。对CRM1的抑制可以调控多个货物蛋白包括肿瘤抑制蛋白、细胞周期调节蛋白以及凋亡相关蛋白等在细胞的定位，达到"一靶多标"的抗肿瘤效果。已报道的CRM1抑制剂均为共价抑制剂。在前期工作中，我们发现了一系列铱络合物和一个小分子药物甲氟喹能抑制CRM1(IC50=1.6-22.1 μm)并能抑制白血病细胞K562(IC50＝0.26-9.80 μm)。这些化合物不含Michael受体，与已报道的CRM1抑制剂的结构特征有本质差异。我们将结合计算机辅助药物设计，对已发现的铱络合物和甲氟喹进行结构优化，通过GST Pull-down实验和细胞实验筛选化合物，通过X-ray晶体衍射实验揭示化合物与CRM1的结合模式，研究优选化合物的抗白血病机制并在动物模型上初步考察化合物的药效与毒性，为靶向CRM1的抗白血病药物的开发提供依据。

CRM1是在多种肿瘤中高表达的出核运输蛋白。抑制CRM1的功能可以调控多个CRM1货物蛋白在细胞的定位，实现抗肿瘤效果。目前已报道的CRM1抑制剂大多为共价抑制剂，然而共价抑制剂通常更容易非特异性结合并产生脱靶效应，从而造成较大的毒副作用。因此，寻找新型的非共价结合的CRM1小分子抑制剂具有重要科学意义和实用价值。在本项目的研究中，我们发现了多个系列的化合物能抑制CRM1并能抑制白血病细胞K562。这些化合物不含Michael受体，且具有新颖的结构骨架。我们结合计算机辅助药物设计，对这些化合物进行结构优化，通过GST Pull-down实验和细胞实验筛选出多个结构新颖，靶向CRM1的抑制剂，我们还通过X-ray晶体衍射实验揭示了这些化合物与CRM1的独特结合模式。此外，在合成目标化合物的过程中，我们开发了多种合成方法，用于增加化合物的结构多样性、优化化合物结构。

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