Synthesis and pharmacological characterization of novel and selective FLT3 inhibitors

新型选择性FLT3抑制剂的合成和药理学表征

• 批准号: 351954221
• 负责人: Professor Dr. Oliver Holger Krämer
• 金额: --
• 依托单位: Institut für Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/351954221?language=en
• 关键词: Synthesis; pharmacological; characterization; novel; selective

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.

大量研究表明，组成型活性fms样酪氨酸激酶-3 （FLT3）突变可导致急性髓性白血病（AML）的发生和进展。这些突变通常位于（FLT3）的近膜结构域。除了这些内部串联复制（ITD）外，激酶结构域的突变也起作用。因此，各种临床研究表明，FLT3酪氨酸激酶活性抑制剂可用于治疗AML。然而，目前使用已知FLT3抑制剂的治疗导致相当比例的患者继发性FLT3突变。这些会导致抑制剂疗效的丧失和患者获益的丧失。我们现在可以提供新的物质BS228。这种化合物具有前所未有的特异性，同时也是迄今为止已知的最高效力。此外，BS228对FLT3-ITD治疗相关突变体起作用。在我们提出的项目中，我们希望巩固我们目前关于BS228的有希望的数据。我们将使用永久性细胞系和原发性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。BS228的化学修饰衍生物旨在产生不可逆抑制剂，并进一步提高选择性、溶解度和生物利用度。在现有工作的基础上，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FLT3-ITD的抑制下被调节，以及它们是否与AML细胞的生长和存活有关，我们还想确定这些参数。这些临床前研究旨在将BS228和潜在的更多这类活性成分带入临床应用。此外，我们希望在分子水平上对FLT3的生物学及其抑制有新的认识。