Inactivation of the NF-κB signaling pathway by inhibition of IKKβ is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. Thienopyrimidine-based analogues were designed through modification of the known IKKβ inhibitor, SPC-839, and then biologically evaluated. The resulting analogues had good inhibitory activity against both nitric oxide and TNF-α, which are well-known inflammatory responses generated by activated NF-κB. However, no inhibitory activity against IKKβ was observed with these compounds. The thienopyrimidine-based analogues were subsequently screened for a target kinase, and FLT3, which is a potential target for acute myeloid leukemia (AML), was identified. Thienopyrimidine-based FLT3 inhibitors showed good inhibition profiles against FLT3 under 1 μM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.
Bibliographical noteFunding Information:
This research was supported by Grants from the Translational Research Center for Protein Function Control ( 2009-0083522 ), the Ministry of Health & Welfare ( A120478 ), the National Research Foundation funded by Ministry of Education ( NRF-2013R1A1A2008165 ) and the Ministry of Science, ICT & Future Planning ( NRF-2006-511-C00060 and NRF-2013M3A6A4072536 ), Republic of Korea, and the Yonsei University Research Fund of 2012.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry