新型PML-RARA抑制剂通过自噬途径诱导APL细胞分化与凋亡的作用机制

三氧化二砷通过靶向降解PML-RARA显著提高了急性早幼粒细胞白血病（APL）的治愈率。最近报道存在砷剂耐药的PML突变热点区，产生耐药的患者缺乏有效治疗药物、死亡率极高。另外，三氧化二砷需静脉滴注给药，且具有一定的毒副作用。然而，其作为无机化合物较难通过修饰改造来克服上述问题。我们前期通过筛选、优化，获得基于有机化合物结构的原创PML-RARA抑制剂MS-036。发现其直接靶向PML结构域，并可克服砷剂耐药。与砷剂不同，MS-036不依赖蛋白酶体途径降解PML-RARA，但可激活自噬信号。本项目拟进一步研究MS-036在细胞和动物模型中对APL细胞分化与凋亡的调控；阐明其与PML-RARA直接结合的模式；探索其如何通过自噬途径降解PML-RARA蛋白；并通过以上结果分析其克服砷剂耐药的机制。项目如期完成，有望为治疗APL提供具有自主知识产权的靶向药物，同时为克服砷剂耐药等问题提供新思路。

The clinical use of arsenic trioxide significantly improved the cure rate of acute promyelocytic leukemia (APL) through degradation of PML-RARA protein. Recently, it has been reported that PML-RARA has a PML mutational hot-spot domain. The patients with arsenic-resistant mutation have a high mortality rate due to lacking effective treatment. Furthermore, arsenic must be intravenously administered in a hospital setting and has some toxicity. However, it is difficult to overcome these problems by modification and synthesis derivatives because arsenic is an inorganic compound. We developed a novel PML-RARA inhibitor based on organic compound by screening and optimization. We demonstrated that MS-036 directly binds to PML moiety of PML-RARA and can overcome arsenic-resistant. In contrast with arsenic, MS-036-induced degradation of PML-RARA is independent on proteasome pathway, but can activate autophagy signal. In this project, we will further confirm the effects of MS-036 on differentiation and apoptosis of APL cell in vitro and in mouse model, elucidate the binding mode of MS-036 with PML-RARA, and clarify the mechanisms of MS-036-induced degradation of PML-RARA through autophagy pathway. Based on these data, a further analysis of the mechanisms of overcoming arsenic-resistant by MS-036 will be conducted as well. This study may offer novel targeted drugs for APL treatment and provide novel therapeutic strategy for overcoming arsenic-resistant issues.