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

  • Bioorg Med Chem Lett. 2014 Jun 15;24(12):2655-60. doi: 10.1016/j.bmcl.2014.04.058.
Chun-Ho Park  1 ,  Chulho Lee  2 ,  Jee Sun Yang  2 ,  Bo-Young Joe  3 ,  Kwangwoo Chun  3 ,  Hyuntae Kim  4 ,  Hye Yun Kim  5 ,  Jong Soon Kang  6 ,  Jangik I Lee  7 ,  Myung-Hwa Kim  8 ,  Gyoonhee Han  9
Affiliations
  • 1. Graduate Program in Biomaterials Science & Engineering, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea; Division of New Drug Development, R&D Center, Jeil Pharmaceutical Co., Ltd 117-1, Keungok-Ri, Baekam-Myun, Cheoin-Gu, Yongin-City, Kyunggi-Do 449-861, Republic of Korea.
  • 2. Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
  • 3. Division of New Drug Development, R&D Center, Jeil Pharmaceutical Co., Ltd 117-1, Keungok-Ri, Baekam-Myun, Cheoin-Gu, Yongin-City, Kyunggi-Do 449-861, Republic of Korea.
  • 4. Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea; Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
  • 5. Center for Neuro-Medicine of Brain Science Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
  • 6. Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk 363-883, Republic of Korea.
  • 7. College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 406-840, Republic of Korea.
  • 8. Division of New Drug Development, R&D Center, Jeil Pharmaceutical Co., Ltd 117-1, Keungok-Ri, Baekam-Myun, Cheoin-Gu, Yongin-City, Kyunggi-Do 449-861, Republic of Korea. Electronic address: [email protected].
  • 9. Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea; Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea. Electronic address: [email protected].
PMID: 24813730 DOI: 10.1016/j.bmcl.2014.04.058
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 1μM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.

Keywords
Acute myeloid leukemia (AML); Anti-inflammation; FLT3; IKKβ; Thienopyrimidine.