For a subpopulation of acute myeloid leukemia (AML) patients, the mutationally activated tyrosine kinase FLT3, has emerged as a promising target for therapy. The development of drug resistance due to mutation is a growing concern for mutant FLT3 inhibitors, such as PKC412, Quizartinib, PLX3397, and Crenolanib. Thus, there is a need to develop novel FLT3 inhibitors that overcome these mutations. Here we report the development of a novel type I ATP competitive inhibitor, JH-IX-179, that is extremely potent and selective for FLT3. JH-IX-179 also has the highest affinity for three constitutively active isoforms of FLT3 (FLT3-ITD, FLT3-N841I, and FLT3-D835V) compared to a panel 456 other kinases. The unique and specific kinase inhibition profile suggests that this chemotype may represent an attractive starting point for the development of further improved FLT3 inhibitors with therapeutic potential in tumors harboring deregulated FLT3 activity.

中文翻译：

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发现一种高效的选择性茚并吲哚酮1型泛FLT3抑制剂。

对于急性髓性白血病（AML）的亚人群，突变激活的酪氨酸激酶FLT3已成为治疗的有希望的靶标。对于突变的FLT3抑制剂（例如PKC412，Quizardinib，PLX3397和Crenolanib），由于突变而引起的耐药性的发展日益引起人们的关注。因此，需要开发克服这些突变的新型FLT3抑制剂。在这里，我们报告了一种新型的I型ATP竞争性抑制剂JH-IX-179的开发，该抑制剂对FLT3具有极强的选择性。与第456个小组的其他激酶相比，JH-IX-179对FLT3的三种组成型活性同工型（FLT3-ITD，FLT3-N841I和FLT3-D835V）也具有最高的亲和力。