Fms‐like tyrosine kinase 3 (FLT3) belongs to the receptor tyrosine kinase family and expressed in hematopoietic progenitor cells. FLT3 gene mutations are reported in ~30% of acute myeloid leukemia cases. FLT3 kinase domain mutation F691L is one of the common causes of acquired resistance to the FLT3 inhibitors including quizartinib. MZH29 and crenolanib were previously reported to inhibit FLT3 F691L. However, crenolanib was reported for the moderate inhibition. We found that Glu661and Asp829 were the most significant residues to target the FLT3 F691L which contribute most significantly to the binding energy with MZH29 and crenolanib. These interactions were found absent with quizartinib. Further free energy landscape analysis revealed that FLT3 F691L bound to MZH29 and crenolanib was more stable as compared to quizartinib.

中文翻译：

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通过FLT3 F691L了解抑制剂的区分

Fms样酪氨酸激酶3（FLT3）属于受体酪氨酸激酶家族，在造血祖细胞中表达。在约30％的急性髓细胞性白血病病例中报告了FLT3基因突变。FLT3激酶结构域突变F691L是对包括Quizartinib在内的FLT3抑制剂产生耐药性的常见原因之一。以前有报道称MZH29和crenolanib抑制FLT3 F691L。然而，据报道克仑诺尼具有中度抑制作用。我们发现，Glu661和Asp829是靶向FLT3 F691L的最重要残基，对与MZH29和crenolanib的结合能贡献最大。发现奎扎替尼不存在这些相互作用。进一步的自由能态分析表明，与基扎替尼相比，结合到MZH29和crenolanib的FLT3 F691L更稳定。