Acute myeloid leukemia (AML) refers to one of the most lethal blood malignancies worldwide. FLT3-ITD mutation is recognized as the most common one that predicted a poorer prognosis. There have been many prominent FLT3-ITD inhibitors approved by the FDA for clinical therapies. However, as impacted by undesirable off-target effects, differentiated metabolic issues, and clinical drug resistance problems, it remains challenging to discover alternative and promising solutions for treating FLT3-ITD⁺ AML. In this study, dovitinib was chemically modified and converted into CRBN-recruiting PROTACs. Two active compounds were identified, which showed enhanced antiproliferative effects against FLT3-ITD⁺ AML cells, both in vitro and in vivo. As demonstrated from further biological evaluation, the compounds could induce the degradation of the FLT3-ITD and KIT proteins in a ubiquitin–proteasome-dependent manner and completely block their downstream signaling pathway. The findings of this study would provide another promising strategy to develop novel therapies for FLT3-ITD⁺ AML.

中文翻译：

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多维替尼的蛋白水解靶向嵌合体 (PROTAC) 修饰增强了对 FLT3-ITD 阳性急性髓系白血病细胞的抗增殖作用

急性髓性白血病 (AML) 是全球最致命的血液恶性肿瘤之一。FLT3-ITD 突变被认为是预测较差预后的最常见突变。有许多著名的 FLT3-ITD 抑制剂被 FDA 批准用于临床治疗。然而，由于受不良脱靶效应、差异化代谢问题和临床耐药性问题的影响，寻找治疗 FLT3-ITD ⁺ AML 的替代和有希望的解决方案仍然具有挑战性。在这项研究中，多维替尼经过化学修饰并转化为 CRBN 招募 PROTAC。鉴定了两种活性化合物，它们在体外和体内均显示出对 FLT3-ITD ⁺ AML 细胞的增强抗增殖作用. 正如进一步的生物学评估所证明的那样，这些化合物可以以泛素-蛋白酶体依赖性方式诱导 FLT3-ITD 和 KIT 蛋白的降解，并完全阻断它们的下游信号通路。这项研究的结果将为开发 FLT3-ITD ⁺ AML 的新疗法提供另一种有希望的策略。