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

Shengyang Cui; Yongjin Wang; Yuting Wang; Xia Tang; Xiaomei Ren; Lei Zhang; Yong Xu; Zhang Zhang; Zhi-Min Zhang; Xiaoyun Lu; Ke Ding

doi:10.1016/j.ejmech.2019.06.064

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. Epub 2019 Jun 25.

Authors

Shengyang Cui¹, Yongjin Wang², Yuting Wang², Xia Tang², Xiaomei Ren², Lei Zhang³, Yong Xu¹, Zhang Zhang⁴, Zhi-Min Zhang⁵, Xiaoyun Lu⁶, Ke Ding⁷

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: zzmoxue@163.com.
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: 13632107756@163.com.
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: luxy2016@jnu.edu.cn.
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: dingke@jnu.edu.cn.

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).

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Benzamides / chemical synthesis
Benzamides / chemistry
Benzamides / pharmacology*
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Membrane Glycoproteins / antagonists & inhibitors*
Membrane Glycoproteins / metabolism
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrazines / chemical synthesis
Pyrazines / chemistry
Pyrazines / pharmacology*
Receptor, trkB / antagonists & inhibitors*
Receptor, trkB / metabolism
Structure-Activity Relationship
Wound Healing / drug effects

Substances

Antineoplastic Agents
Benzamides
Imidazoles
Membrane Glycoproteins
Protein Kinase Inhibitors
Pyrazines
2-methylbenzamide
Receptor, trkB
tropomyosin-related kinase-B, human