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FLT3 inhibitors (FLT3i) are widely used to treat acute myeloid leukemia (AML), but adaptive and acquired resistance remains a primary challenge. Therefore, inhibitors simultaneously blocking adaptive and acquired resistance are highly demanded. Here, we observed the potential of CHK1 inhibitors to synergistically improve the therapeutic effect of FLT3i in FLT3-mutated AML cells. Moreover, 30 showed favourable druggability without significant blood toxicity or myelosuppression and exhibited an excellent oral PK profile with a T1/2 over 12 h in beagles. These findings support the targeting of FLT3 and CHK1 as a novel strategy for overcoming adaptive and acquired resistance to FLT3i therapy in AML and suggest 30 as a potential clinical candidate.
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