Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKβ inhibitors

Chun Ho Park, Chulho Lee, Jee Sun Yang, Bo Young Joe, Kwangwoo Chun, Hyuntae Kim, Hye Yun Kim, Jong Soon Kang, Jangik I. Lee, Myung Hwa Kim, Gyoonhee Han

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2655-2660
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number12
DOIs
Publication statusPublished - 2014 Jun 15

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Park, C. H., Lee, C., Yang, J. S., Joe, B. Y., Chun, K., Kim, H., Kim, H. Y., Kang, J. S., Lee, J. I., Kim, M. H., & Han, G. (2014). Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKβ inhibitors. Bioorganic and Medicinal Chemistry Letters, 24(12), 2655-2660. https://doi.org/10.1016/j.bmcl.2014.04.058