FLT3 (FMS-Like Tyrosine kinase) is a member of the class III receptor tyrosine kinase family which plays an important role in the development of hematopoietic systems. Most FLT3 mutations arise from ITDs (internal tandem duplications) formed in the juxtamembrane domain which stimulates activation of FLT3. FLT3/ITD frequently occurs in AML (acute myeloid leukemia). Currently, several small molecule of FLT3 inhibitors acquired drug resistances during clinical trials caused by secondary mutations within the FLT3/ITD cells. Therefore, development of new FLT3 inhibitors are needed to ensure clinical applicability for AML.We have designed and synthesized diverse thieno[2,3-d]pyrimidine compounds by introducing a variety of substituents at the 2, 4, 5 and 6-positions to discover selective FLT3 inhibitors. All 34 synthesized compounds were assayed for FLT3 kinase activity and further evaluated for growth inhibition on 2 leukemia cell lines (MV4-11, THP1) and 6 solid tumor cell lines (ACHN, HCT15, NCI-H23, PC-3, NUGC-3 and MDA-MB-231). The results of FLT3 inhibitory activities led to 4 compounds, some which exhibited better growth inhibition of FLT3-mutated MV4-11 cells than FLT3 inhibitor Quizartinib. Especially, 18a which only showed significant growth inhibition against the MV4-11 cells, which indicates potent selectivity against FLT3/ITD AML cells.FLT3 has been considered as a potential molecular target for the treatment of AML. Our study was focused on the discovery of selective FLT3 inhibitors, resulting in the development of 18a which showed good FLT3 inhibitory activity as well as selectivity on the FLT/ITD AML cell lines. Figure 1. <img src='https://acs-archive-assets2.s3.amazonaws.com/241nm/uploads/71176_kelsey_thymidine.jpg' alt='' />

Design, synthesis, and biological evaluation of selective FLT3 inhibitors for the treatment of acute myeloid leukemia

248th National Meeting (2014)

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