Inactivation of the NF-?B signaling pathway by inhibition of IKK� is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. To discover new IKK� inhibitors, known IKK� inhibitor SPC-839   was modified by introducing a thienopyrimidine core and then biologically evaluated. Resulting analogues had good inhibitory activities against both nitric oxide and TNF-a, which are well-known inflammatory responses generated by activated NF-?B. However no promising inhibitory activities against IKK� were observed. To probe the target of thienopyrimidine-based analogues, we carried out a kinase panel assay and FLT3 was identified as the target. Thienopyrimidine-based analogues showed good inhibition profiles against FLT3 under 1�M as well as good cell growth inhibitory activities on leukemia cell lines. Overall, these compounds represent promising inhibitors for the future development of a treatment for acute myeloid leukemia (AML).

Design and synthesis of thienopyrimidine based FLT3 inhibitors from SPC-839, a known IKK� inhibitor

248th National Meeting (2014)

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