Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Division of Hematology/Oncology, University of California, San Francisco, CA, USA.
Bioorg Chem. 2024 Feb;143:106966. doi: 10.1016/j.bioorg.2023.106966. Epub 2023 Nov 11.
Activating mutations within FLT3 make up 30 % of all newly diagnosed acute myeloid leukemia (AML) cases, with the most common mutation being an internal tandem duplication (FLT3-ITD) in the juxtamembrane region (25 %). Currently, two generations of FLT3 kinase inhibitors have been developed, with three inhibitors clinically approved. However, treatment of FLT3-ITD mutated AML is limited due to the emergence of secondary clinical resistance, caused by multiple mechanism including on-target FLT3 secondary mutations - FLT3-ITD/D835Y and FLT3-ITD/F691L being the most common, as well as the off-target activation of alternative pathways including the BCR-ABL pathway. Through the screening of imidazo[1,2-a]pyridine derivatives, N-(3-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine (compound 1) was identified as an inhibitor of both the FLT3-ITD and BCR-ABL pathways. Compound 1 potently inhibits clinically related leukemia cell lines driven by FLT3-ITD, FLT3-ITD/D835Y, FLT3-ITD/F691L, or BCR-ABL. Studies indicate that it mediates proapoptotic effects on cells by inhibiting FLT3 and BCR-ABL pathways, and other possible targets. Compound 1 is more potent against FLT3-ITD than BCR-ABL, and it may have other possible targets; however, compound 1 is first step for further optimization for the development of a balanced FLT3-ITD/BCR-ABL dual inhibitor for the treatment of relapsed FLT3-ITD mutated AML with multiple secondary clinical resistant subtypes such as FLT3-ITD/D835Y, FLT3-ITD/F691L, and cells co-expressing FLT3-ITD and BCR-ABL.
FLT3 中的激活突变构成了所有新诊断的急性髓系白血病 (AML) 病例的 30%，最常见的突变是在跨膜区的内部串联重复 (FLT3-ITD)(25%)。目前已经开发了两代 FLT3 激酶抑制剂，其中有三种抑制剂已获得临床批准。然而，由于多种机制导致的继发性临床耐药的出现，FLT3-ITD 突变的 AML 的治疗受到限制，这些机制包括靶标 FLT3 继发性突变-FLT3-ITD/D835Y 和 FLT3-ITD/F691L 是最常见的，以及非靶标激活的替代途径，包括 BCR-ABL 途径。通过对咪唑并[1,2-a]吡啶衍生物的筛选，鉴定出 N-(3-甲氧基苯基)-6-(7-(1-甲基-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)吡啶-2-胺（化合物 1）为同时抑制 FLT3-ITD 和 BCR-ABL 途径的抑制剂。化合物 1 能够强烈抑制由 FLT3-ITD、FLT3-ITD/D835Y、FLT3-ITD/F691L 或 BCR-ABL 驱动的临床相关白血病细胞系。研究表明，它通过抑制 FLT3 和 BCR-ABL 途径以及其他可能的靶点，对细胞产生促凋亡作用。化合物 1 对 FLT3-ITD 的抑制作用强于 BCR-ABL，并且可能有其他可能的靶点；然而，化合物 1 是进一步优化为开发用于治疗具有多种继发性临床耐药亚型（如 FLT3-ITD/D835Y、FLT3-ITD/F691L 和同时表达 FLT3-ITD 和 BCR-ABL 的细胞）的复发 FLT3-ITD 突变的 AML 的平衡的 FLT3-ITD/BCR-ABL 双重抑制剂的第一步。
