2. Academic Validation
  3. Design, synthesis and biological evaluation of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides as potent and selective pan-tropomyosin receptor kinase (TRK) inhibitors

Design, synthesis and biological evaluation of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides as potent and selective pan-tropomyosin receptor kinase (TRK) inhibitors

  • Eur J Med Chem. 2019 Oct 1:179:470-482. doi: 10.1016/j.ejmech.2019.06.064.
Shengyang Cui 1,  Yongjin Wang 2,  Yuting Wang 2,  Xia Tang 2,  Xiaomei Ren 2,  Lei Zhang 3,  Yong Xu 1,  Zhang Zhang 4,  Zhi-Min Zhang 5,  Xiaoyun Lu 6,  Ke Ding 7
Affiliations

Affiliations

  • 1 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou, 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing, 100049, China.
  • 2 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632, China.
  • 3 National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai, 201210, China.
  • 4 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: [email protected].
  • 5 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: [email protected].
  • 6 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: [email protected].
  • 7 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: [email protected].
PMID: 31271959 DOI: 10.1016/j.ejmech.2019.06.064
Abstract

A series of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides was designed and synthesized as new tropomyosin receptor kinases (Trks) inhibitors by utilizing a structure-guided optimization strategy. One of the most potent compounds 9o suppressed TrkA/B/C with IC50 values of 2.65, 10.47 and 2.95 nM, respectively. The compound dose-dependently inhibited brain-derived neurotrophic factor (BDNF)-mediated TrkB activation and suppressed migration and invasion of SH-SY5Y-TrkB neuroblastoma cells expressing high level of TrkB. Inhibitor 9o also inhibited the proliferation of SH-SY5Y-TrkB cells with an IC50 value of 58 nM, which was comparable to that of an US FDA recently approved drug LOXO-101. Compound 9o may serve as a new lead compound for further anti-cancer drug discovery.

Keywords

Cancer; Inhibitor; Neuroblastoma; Tropomyosin receptor kinases(Trks).

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