Abstract：
Mutation of FLT3 protein kinase is often associated with deregulated cell proliferation in acute myeloid leukemia and the inhibition of this kinase is a potential therapeutic strategy. We report a novel series of 3,5,7-trisubstituted pyrazolo[1,5-a]pyrimidines prepared in an effort to study their biological activity particularly toward FLT3-ITD and its downstream regulators as well as toward CDK2 and CDK9. Derivative 10b was capable to strongly inhibit all kinases and its selectivity in FLT3-ITD expressing cell lines MOLM13 and MV4-11 was in line with FLT3-ITD inhibition. Further biochemical analyses and molecular docking confirmed FLT3 as a cellular target of 10b.
摘要：
FLT3蛋白激酶的突变通常与急性髓性白血病中细胞增殖失调有关，抑制该激酶是一种潜在的治疗策略。我们报道了一系列新的3,5,7-三取代的吡唑并[1,5-a]嘧啶，旨在研究它们的生物活性，特别是对FLT3-ITD及其下游调节剂以及CDK2和CDK9的生物活性。衍生物10b能够强烈抑制所有激酶,并且其在表达FLT3-ITD的细胞系MOLM13和MV4-11中的选择性与FLT3-ITD抑制一致。进一步的生化分析和分子对接证实FLT3是10b的细胞靶标。
