2. Academic Validation
  3. Design, synthesis and biological evaluation of macrocyclic derivatives as TRK inhibitors

Design, synthesis and biological evaluation of macrocyclic derivatives as TRK inhibitors

  • Bioorg Med Chem Lett. 2021 Dec 1;53:128409. doi: 10.1016/j.bmcl.2021.128409.
Pei Li 1,  Shi Cai 2,  Tong Zhao 1,  Lin Xu 1,  Dezhong Guan 2,  Jinruo Li 3,  Jinpei Zhou 4,  Huibin Zhang 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
  • 2 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
  • 3 College of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
  • 4 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: [email protected].
  • 5 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: [email protected].
PMID: 34628036 DOI: 10.1016/j.bmcl.2021.128409
Abstract

Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are transmembrane Receptor Tyrosine Kinases, which are respectively encoded by NTRK1, NTRK2, and NTRK3 genes. Herein, we reported the design, synthesis and Structure-Activity Relationship (SAR) investigation of a series of macrocyclic derivatives as new TRK inhibitors. Among these compounds, compound 9e exhibited strong kinase inhibitory activity (TRKG595R IC50 = 13.1 nM) and significant antiproliferative activity in the Ba/F3-LMNA-NTRK1 cell line (IC50 = 0.080 μM) and compound 9e has shown a better inhibitory effect (IC50 = 0.646 μM) than control drug LOXO-101 in Ba/F3-LMNA-NTRK1-G595R cell line. These results indicate that compound 9e is a potential Trk Inhibitor for further investigation.

Keywords

Molecular docking; Synthesis; TRK inhibitors; Tropomyosin receptor kinases.

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