Synthesis and biological evaluation of novel thieno[2,3-d]pyrimidine-based FLT3 inhibitors as anti-leukemic agents

• Novel 22 thieno[2,3-d]pyrimidine-based analogs were designed and synthesized.
• Thieno[2,3-d]pyrimidine-based analogs showed good FLT3 inhibitory activities.
• Relatively simple groups at the C6 position enhanced FLT3 inhibitory activity.
• Three compounds potently inhibited the TKD point mutant D835Y as well as FLT3/ITD.
• Compound 17a emerged as the most promising anti-leukemic agent.

The most common mutations in acute myeloid leukemia (AML) are those that cause the activation of FMS-like tyrosine kinase 3 (FLT3). Therefore, FLT3 is regarded as a potential target for the treatment of AML. A novel series of thieno[2,3-d]pyrimidine-based analogs was designed and synthesized as FLT3 inhibitors. All synthesized compounds were assayed for the tyrosine kinase activity of FLT3 and growth inhibitory activity in four human leukemia cell lines (THP1, MV4-11, K562, and HL-60). Among these compounds, compound 17a, which possesses relatively short and simple substituents at the C6 position of thieno[2,3-d]pyrimidine, emerged as the most promising anti-leukemic agent. Compound 17a exhibited potent inhibition of FLT3-positive leukemic cell growth and of the FLT3 D835Y kinase; such inhibition is required for the successful treatment of AML. The data supports the further investigation of this class of compounds as potential anti-leukemic agents.

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