2. Academic Validation
  3. Design, synthesis, and Structure-Activity Relationships (SAR) of 3-vinylindazole derivatives as new selective tropomyosin receptor kinases (Trk) inhibitors

Design, synthesis, and Structure-Activity Relationships (SAR) of 3-vinylindazole derivatives as new selective tropomyosin receptor kinases (Trk) inhibitors

  • Eur J Med Chem. 2020 Oct 1;203:112552. doi: 10.1016/j.ejmech.2020.112552.
Yunxin Duan 1,  Jie Wang 1,  Sihua Zhu 1,  Zheng-Chao Tu 2,  Zhang Zhang 3,  Shingpan Chan 4,  Ke Ding 5
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemistry Drug Development, School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632, 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 Chemistry Drug Development, School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632, China; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, 510530, China.
  • 3 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemistry Drug Development, School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: [email protected].
  • 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 Chemistry 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 Chemistry Drug Development, School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: [email protected].
PMID: 32702585 DOI: 10.1016/j.ejmech.2020.112552
Abstract

Neurotrophic receptor tyrosine kinase (NTRK) fusions are oncogenic drivers for a variety of adult and pediatric tumors, validated by the US FDA approval of small molecular Trk inhibitors Larotrectinib (1, LOXO-101) and Entrectinib (2). However, gene mutation mediated resistance becomes a major challenge for Trk Inhibitor therapies. Herein, we report the design, synthesis and Structure-Activity Relationship investigation of a series of 3-vinylindazole derivatives as new Trk inhibitors with low nanomolar potencies. A representative compound, 7mb, binds to TrkA/B/C with Kd values of 1.6, 3.1 and 4.9 nM, and suppresses their kinase functions with IC50 values of 1.6, 2.9 and 2.0 nM, respectively, but is obviously less potent for the majority of a panel of 403 wild-type kinases in a KINOMEscan selectivity investigation. The compound also potently suppresses proliferation of a panel of BaF3 cells stably transformed with NTRK fusions with IC50 values in low nM ranges. Additionally, the compound exhibits strong inhibition against the Larotrectinib-resistant cells with NTRK1-G667C or NTRK3-G696A mutations with IC50 values of 0.031 and 0.018 μM, respectively. Although the relatively poor oral bioavailability of 7mb will limit its further development, this compound may be utilized a lead molecule for further structural optimization.

Keywords

Fusion; Inhibitor; Mutation; Neurotrophic receptor tyrosine kinase gene (NTRK); Resistance; Tropomyosin receptor kinase (Trk).

Figures
Products