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Design, synthesis and biological activity of bicyclic carboxamide derivatives as TRK inhibitors.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 Dec 01; Vol. 28 (23), pp. 115811. Date of Electronic Publication: 2020 Oct 10. - Publication Year :
- 2020
-
Abstract
- 'precision medicine' is characterized by the selection of targeted drugs based on genetic characteristics of tumor from patients, and no longer selected basis on the type of cancer tissue. Among them, clinical trials on neurotrophin receptor tyrosine kinase genes (NTRK) have proven that great anti-cancer effects can be achieved in different cancer patients. In this paper, a novel total of twenty compounds in two categories have been designed and synthesized. Results of Kinase activity tests showed that I-9 (TRKA IC <subscript>50</subscript> = 1.3 nM, TRKA <superscript>G595R</superscript> IC <subscript>50</subscript> = 6.1 nM), and I-10 (TRKA IC <subscript>50</subscript> = 1.1 nM, TRKA <superscript>G595R</superscript> IC <subscript>50</subscript> = 5.3 nM) have significant inhibitory activity, and results of cell viability tests showed that I-9 and I-10 can maintain a great inhibitory effect in the Ba/F3-LMNA-NTRK1 cell line(IC <subscript>50</subscript> = 81.1 nM and 41.7 nM, respectively), and in Ba/F3-LMNA-NTRK1-G595R cell line, I-9 and I-10 have better cell activity (IC <subscript>50</subscript> was 495.3 nM, 336.6 nM, respectively) compared with the positive control drug LOXO-101. These results indicate that I-9 and I-10 are potential TRK inhibitors that can overcome drug resistance for further investigation.<br /> (Copyright © 2020. Published by Elsevier Ltd.)
- Subjects :
- Amides metabolism
Amides pharmacology
Binding Sites
Cell Line, Tumor
Cell Survival drug effects
Humans
Molecular Docking Simulation
Polymorphism, Single Nucleotide
Protein Kinase Inhibitors metabolism
Protein Kinase Inhibitors pharmacology
Receptor, trkA genetics
Receptor, trkA metabolism
Structure-Activity Relationship
Amides chemistry
Bridged Bicyclo Compounds chemistry
Drug Design
Protein Kinase Inhibitors chemical synthesis
Receptor, trkA antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 28
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33069129
- Full Text :
- https://doi.org/10.1016/j.bmc.2020.115811