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

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

  • Eur J Med Chem. 2014 Oct 6:85:399-407. doi: 10.1016/j.ejmech.2014.08.001.
Jee Sun Yang 1,  Chun-Ho Park 2,  Chulho Lee 1,  Hwan Kim 1,  Changmok Oh 1,  Yejoo Choi 1,  Jong Soon Kang 3,  Jieun Yun 3,  Jin-Hyun Jeong 4,  Myung-Hwa Kim 5,  Gyoonhee Han 6
Affiliations

Affiliations

  • 1 Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
  • 2 Graduate Program in Biomaterials Science & Engineering, Yonsei University, Seoul 120-749, Republic of Korea.
  • 3 Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk 363-883, Republic of Korea.
  • 4 College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Yeonsu-gu, Incheon 406-840, Republic of Korea.
  • 5 Korea Drug Development Fund, 14th Fl, KT&G SeodaemunTower, 21-1, Migeun-dong, Seodaemun-gu, Seoul, Republic of Korea.
  • 6 Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea; Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seoul 120-749, Republic of Korea. Electronic address: gyoonhee@yonsei.ac.kr.
PMID: 25108079 DOI: 10.1016/j.ejmech.2014.08.001
Abstract

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.

Keywords

Acute myeloid leukemia (AML); D835Y; FMS-like tyrosine kinase 3 (FLT3); Internal tandem duplications (ITD); Thieno[2,3-d]pyrimidine.

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