Hesham Heba M, Dokla Eman M E, Elrazaz Eman Z, Lasheen Deena S, Abou El Ella Dalal A
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt.
Eur J Med Chem. 2024 Nov 5;277:116717. doi: 10.1016/j.ejmech.2024.116717. Epub 2024 Aug 1.
The urgent and unmet medical demand of acute myeloid leukemia (AML) patients has driven the drug discovery process for expansion of the landscape of AML treatment. Despite the several agents developed for treatment of AML, more than 60 % of treated patients undergo relapse again after re-emission, thus, no complete cure for this complex disease has been reached yet. Targeted oncoprotein degradation is a new paradigm that can be employed to solve drug resistance, disease relapse, and treatment failure in complex diseases as AML, the most lethal hematological malignancy. AML is an aggressive blood cancer form and the most common type of acute leukemia, with bad outcomes and a very poor 5-year survival rate. FLT3 mutations occur in about 30 % of AML cases and FLT3-ITD is associated with poor prognosis of this disease. Prevalent FLT3 mutations include internal tandem duplication and point mutations (e.g., D835) in the tyrosine kinase domain, which induce FLT3 kinase activation and result in survival and proliferation of AML cells again. Currently approved FLT3 inhibitors suffer from limited clinical efficacy due to FLT3 reactivation by mutations, therefore, alternative new treatments are highly needed. Proteolysis-targeting chimera (PROTAC) is a bi-functional molecule that consists of a ligand of the protein of interest, FLT3 inhibitor in our case, that is covalently linked to an E3 ubiquitin ligase ligand. Upon FLT3-specific PROTAC binding to FLT3, the PROTAC can recruit E3 for FLT3 ubiquitination, which is subsequently subjected to proteasome-mediated degradation. In this review we tried to address the question if PROTAC technology has succeeded in tackling the disease relapse and treatment failure of AML. Next, we explored the latest FLT3-targeting PROTACs developed in the past few years such as quizartinib-based PROTACs, dovitinib-based PROTACs, gilteritinib-based PROTACs, and others. Then, we followed with a deep analysis of their advantages regarding potency improvement and overcoming AML drug resistance. Finally, we discussed the challenges facing these chimeric molecules with proposed future solutions to circumvent them.
急性髓系白血病（AML）患者迫切且未得到满足的医疗需求推动了AML治疗格局拓展的药物研发进程。尽管已开发出多种用于治疗AML的药物，但超过60%的接受治疗的患者在缓解后会再次复发，因此，对于这种复杂疾病尚未实现完全治愈。靶向癌蛋白降解是一种新的模式，可用于解决AML（最致命的血液系统恶性肿瘤）等复杂疾病中的耐药性、疾病复发和治疗失败问题。AML是一种侵袭性血液癌症形式，也是最常见的急性白血病类型，预后不良，5年生存率极低。约30%的AML病例存在FLT3突变，FLT3-ITD与该疾病的不良预后相关。常见的FLT3突变包括内部串联重复以及酪氨酸激酶结构域中的点突变（如D835），这些突变会诱导FLT3激酶激活，导致AML细胞再次存活和增殖。目前获批的FLT3抑制剂由于突变导致FLT3重新激活，临床疗效有限，因此，迫切需要替代性的新治疗方法。蛋白酶靶向嵌合体（PROTAC）是一种双功能分子，由感兴趣的蛋白质（在我们的案例中为FLT3抑制剂）的配体与E3泛素连接酶配体共价连接而成。当FLT3特异性PROTAC与FLT3结合后，PROTAC可招募E3对FLT3进行泛素化，随后该泛素化产物会被蛋白酶体介导降解。在本综述中，我们试图探讨PROTAC技术是否成功解决了AML的疾病复发和治疗失败问题。接下来，我们研究了过去几年开发的最新的靶向FLT3的PROTAC，如基于quizartinib的PROTAC、基于dovitinib的PROTAC、基于gilteritinib的PROTAC等。然后，我们深入分析了它们在提高效力和克服AML耐药性方面的优势。最后，我们讨论了这些嵌合分子面临的挑战，并提出了未来规避这些挑战的解决方案。
