Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis-targeting chimeras (PROTACs) represent a promising approach to eliminate the resistance of FLT3 inhibitors. However, due to the poor druggability of PROTACs, the development of orally bioavailable FLT3-PROTACs faces great challenges. Herein, a novel orally bioavailable FLT3-ITD degrader A20 with excellent pharmacokinetic properties was discovered through reasonable design. A20 selectively inhibited the proliferation of FLT3-ITD mutant acute myeloid leukemia (AML) cells and potently induced FLT3-ITD degradation through the ubiquitin–proteasome system. Notably, oral administration of A20 resulted in complete tumor regression on subcutaneous AML xenograft models. Furthermore, on systemic AML xenograft models, A20 could completely eliminate the CD45⁺CD33⁺ human leukemic cells in murine and significantly prolonged the survival time of mice. Most importantly, A20 exerted significantly improved antiproliferative activity against drug-resistant AML cells compared to existing FLT3 inhibitors. These findings suggested that A20 could serve as a promising drug candidate for relapsed or refractory AML.

中文翻译：

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发现一种新型口服生物可利用的 FLT3-PROTAC 降解剂，可有效治疗急性髓系白血病并克服 FLT3 抑制剂的耐药性

Fms 样酪氨酸受体激酶 3 (FLT3) 蛋白水解靶向嵌合体 (PROTAC) 代表了消除 FLT3 抑制剂耐药性的一种有前景的方法。然而，由于PROTACs的成药性较差，口服生物可利用的FLT3-PROTACs的开发面临着巨大的挑战。在此，通过合理的设计，发现了一种具有优异药代动力学特性的新型口服生物可利用的FLT3-ITD降解剂A20 。 A20选择性抑制 FLT3-ITD 突变型急性髓系白血病 (AML) 细胞的增殖，并通过泛素-蛋白酶体系统有效诱导 FLT3-ITD 降解。值得注意的是，口服A20可使皮下 AML 异种移植模型的肿瘤完全消退。此外，在全身性AML异种移植模型上，A20可以完全消除小鼠体内的CD45 ⁺ CD33 ⁺人类白血病细胞，并显着延长小鼠的生存时间。最重要的是，与现有的 FLT3 抑制剂相比， A20对耐药 AML 细胞的抗增殖活性显着提高。这些发现表明A20可以作为治疗复发或难治性 AML 的有前途的候选药物。