Synthesis and pharmacological characterization of novel and selective FLT3 inhibitors

大量研究表明，FMS样酪氨酸激酶-3(Flt3)基因突变在急性髓系白血病(AML)的发生发展中起重要作用。这些突变经常存在于(Flt3)的膜旁区域。除了这些内部串联复制(ITD)之外，激酶结构域的突变也起到了一定的作用。因此，各种临床研究表明，Flt3酪氨酸激酶活性的抑制剂对AML的治疗是有用的。然而，目前使用已知的Flt3抑制剂的治疗方法会在相当大比例的患者中导致继发性flt3突变。这些都会导致抑制剂效力的丧失和患者利益的丧失。我们现在能够提供新的物质BS228。这种化合物具有前所未有的专一性，同时也是迄今已知的最高效力。此外，BS228对治疗相关的Flt3-ITD突变起作用。在我们提议的项目中，我们想要巩固我们目前在BS228上有希望的数据。我们将使用永久细胞系和原代白血病细胞进行结构和细胞生物学研究。动物模型也应包括在内。将产生和分析BS228的化学修饰的衍生物，旨在产生不可逆转的抑制剂，并进一步提高选择性、溶解性和生物利用度。在我们现有工作的基础上，我们还希望进一步研究针对Flt3-ITD阳性AML的合理联合方案。由于目前还不完全清楚哪些信号通路在抑制Flt3-ITD后被调节，以及它们是否与AML细胞的生长和生存相关，我们还想定义这些参数。这些临床前研究的目的是使BS228和潜在的更有效的这种类型的成分进入临床应用。此外，我们希望在分子水平上对Flt3的生物学及其抑制获得新的见解。

Numerous studies demonstrate that constitutively active Fms-Like Tyrosine Kinase-3 (FLT3) mutations causally contribute to the development and progression of acute myeloid leukemia (AML). These mutations frequently reside in the juxtamembrane domain of (FLT3). In addition to these internal tandem duplications (ITD), mutations in the kinase domain play a role. Accordingly, various clinical studies show that inhibitors of the tyrosine kinase activity of FLT3 are useful for the treatment of AML. However, the current therapy with known FLT3 inhibitors leads to secondary FLT3 mutations in a substantial proportion of patients. These cause a loss of inhibitor efficacy and a lost benefit for the patients. We are now able to offer the new substance BS228. This compound has an unprecedented specificity and at the same time the highest potency known to date. Furthermore, BS228 acts against therapy-associated mutants of FLT3-ITD. In our proposed project we want to consolidate our present, promising data on BS228. We will employ structural and cell biological studies using permanent cell lines and primary leukemia cells. Animal models shall also be included. Chemically modified derivatives of BS228 that aim to yield irreversible inhibitors and to further improve the selectivity, solubility, and bioavailability will be generated and analyzed. Based on our existing work, we also want to investigate further rational combination regimen against FLT3-ITD-positive AML. Since it has not been fully understood, which signaling pathways are modulated upon the inhibition of FLT3-ITD and whether they are relevant for the growth and survival of AML cells, we additionally want to define these parameters. These preclinical investigations aim to bring BS228 and potentially even more active ingredients of this type into clinical application. Moreover, we want to gain new insights into the biology of FLT3 and its inhibition at the molecular level.