Division of Oncology and.
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
J Clin Invest. 2020 Apr 1;130(4):2017-2023. doi: 10.1172/JCI127907.
Tyrosine kinase domain (TKD) mutations contribute to acquired resistance to FMS-like tyrosine kinase 3 (FLT3) inhibitors used to treat FLT3-mutant acute myeloid leukemia (AML). We report a cocrystal structure of FLT3 with a type I inhibitor, NCGC1481, that retained potent binding and activity against FLT3 TKD and gatekeeper mutations. Relative to the current generation of advanced FLT3 inhibitors, NCGC1481 exhibited superior antileukemic activity against the common, clinically relevant FLT3-mutant AML cells in vitro and in vivo.
酪氨酸激酶结构域（TKD）突变导致对 FMS 样酪氨酸激酶 3（FLT3）抑制剂的获得性耐药，这些抑制剂用于治疗 FLT3 突变型急性髓系白血病（AML）。我们报告了 FLT3 与 I 型抑制剂 NCGC1481 的共晶结构，该抑制剂对 FLT3 TKD 和守门员突变仍保持强大的结合和活性。与当前一代先进的 FLT3 抑制剂相比，NCGC1481 在体外和体内对常见的、临床上相关的 FLT3 突变型 AML 细胞具有更好的抗白血病活性。
