Beyer Mandy, Henninger Sven J, Haehnel Patricia S, Mustafa Al-Hassan M, Gurdal Ece, Schubert Bastian, Christmann Markus, Sellmer Andreas, Mahboobi Siavosh, Drube Sebastian, Sippl Wolfgang, Kindler Thomas, Krämer Oliver H
Department of Toxicology, University Medical Center, 55131 Mainz, Germany.
Department of Hematology, Medical Oncology, and Pneumology, University Medical Center, 55131 Mainz, Germany; University Cancer Center, University Medical Center, Mainz, Germany; German Consortia for Translational Cancer Research, 55131 Mainz, Germany.
Cell Chem Biol. 2022 Mar 17;29(3):398-411.e4. doi: 10.1016/j.chembiol.2021.10.011. Epub 2021 Nov 10.
Internal tandem duplications (ITDs) in the FMS-like tyrosine kinase-3 (FLT3) are causally linked to acute myeloid leukemia (AML) with poor prognosis. Available FLT3 inhibitors (FLT3i) preferentially target inactive or active conformations of FLT3. Moreover, they co-target kinases for normal hematopoiesis, are vulnerable to therapy-associated tyrosine kinase domain (TKD) FLT3 mutants, or lack low nanomolar activity. We show that the tyrosine kinase inhibitor marbotinib suppresses the phosphorylation of FLT3-ITD and the growth of permanent and primary AML cells with FLT3-ITD. This also applies to leukemic cells carrying FLT3-ITD/TKD mutants that confer resistance to clinically used FLT3i. Marbotinib shows high selectivity for FLT3 and alters signaling, reminiscent of genetic elimination of FLT3-ITD. Molecular docking shows that marbotinib fits in opposite orientations into inactive and active conformations of FLT3. The water-soluble marbotinib-carbamate significantly prolongs survival of mice with FLT3-driven leukemia. Marbotinib is a nanomolar next-generation FLT3i that represents a hybrid inhibitory principle.
FMS样酪氨酸激酶3（FLT3）内部串联重复（ITD）与预后不良的急性髓系白血病（AML）存在因果关系。现有的FLT3抑制剂（FLT3i）优先靶向FLT3的无活性或活性构象。此外，它们还共同靶向正常造血所需的激酶，易受治疗相关酪氨酸激酶结构域（TKD）FLT3突变体的影响，或者缺乏低纳摩尔活性。我们发现酪氨酸激酶抑制剂马博替尼可抑制FLT3-ITD的磷酸化以及携带FLT3-ITD的永久性和原发性AML细胞的生长。这同样适用于携带对临床使用的FLT3i产生耐药性的FLT3-ITD/TKD突变体的白血病细胞。马博替尼对FLT3具有高度选择性，并改变信号传导，类似于对FLT3-ITD进行基因消除的效果。分子对接显示，马博替尼以相反的方向适配FLT3的无活性和活性构象。水溶性马博替尼-氨基甲酸酯可显著延长FLT3驱动的白血病小鼠的生存期。马博替尼是一种纳摩尔级的下一代FLT3i，代表了一种混合抑制原理。
