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

Pei Li; Shi Cai; Tong Zhao; Lin Xu; Dezhong Guan; Jinruo Li; Jinpei Zhou; Huibin Zhang

doi:10.1016/j.bmcl.2021.128409

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. Epub 2021 Oct 7.

Authors

Pei Li¹, Shi Cai², Tong Zhao¹, Lin Xu¹, Dezhong Guan², Jinruo Li³, Jinpei Zhou⁴, Huibin Zhang⁵

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: jpzhou668@163.com.
⁵ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: zhanghb80@cpu.edu.cn.

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 (TRK^G595R 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Macrocyclic Compounds / chemical synthesis
Macrocyclic Compounds / chemistry
Macrocyclic Compounds / pharmacology*
Membrane Glycoproteins / antagonists & inhibitors*
Membrane Glycoproteins / metabolism
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Receptor, trkA / antagonists & inhibitors*
Receptor, trkA / metabolism
Receptor, trkB / antagonists & inhibitors*
Receptor, trkB / metabolism
Receptor, trkC / antagonists & inhibitors*
Receptor, trkC / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Macrocyclic Compounds
Membrane Glycoproteins
NTRK1 protein, human
NTRK3 protein, human
Protein Kinase Inhibitors
Receptor, trkA
Receptor, trkB
Receptor, trkC
tropomyosin-related kinase-B, human