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Discovery of pyrazolo-thieno[3,2-d]pyrimidinylamino-phenyl acetamides as type-II pan-tropomyosin receptor kinase (TRK) inhibitors: Design, synthesis, and biological evaluation.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2021 Apr 15; Vol. 216, pp. 113265. Date of Electronic Publication: 2021 Feb 09. - Publication Year :
- 2021
-
Abstract
- Tropomyosin receptor kinase (TRK) represents an attractive oncology target for cancer therapy related to its critical role in cancer formation and progression. NTRK fusions are found to occur in 3.3% of lung cancers, 2.2% of colorectal cancers, 16.7% of thyroid cancers, 2.5% of glioblastomas, and 7.1% of pediatric gliomas. In this paper, we described the discovery of the type-II pan-TRK inhibitor 4c through the structure-based drug design strategy from the original hits 1b and 2b. Compound 4c exhibited excellent in vitro TRKA, TRKB, and TRKC kinase inhibitory activity and anti-proliferative activity against human colorectal carcinoma derived cell line KM12. In the NCI-60 human cancer cell lines screen, compound 4g demonstrated nearly 80% of growth inhibition for KM12, while only minimal inhibitory activity was observed for the remaining 59 cancer cell lines. Western blot analysis demonstrated that 4c and its urea cousin 4k suppressed the TPM3-TRKA autophosphorylation at the concentrations of 100 nM and 10 nM, respectively. The work presented that 2-(4-(thieno[3,2-d]pyrimidin-4-ylamino)phenyl)acetamides could serve as a novel scaffold for the discovery and development of type-II pan-TRK inhibitors for the treatment of TRK driven cancers.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Acetamides metabolism
Acetamides pharmacology
Binding Sites
Blood-Brain Barrier drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Phosphorylation drug effects
Protein Kinase Inhibitors metabolism
Protein Kinase Inhibitors pharmacology
Pyrazoles chemistry
Pyrimidines chemistry
Receptor, trkA metabolism
Receptor, trkB metabolism
Structure-Activity Relationship
Acetamides chemistry
Drug Design
Protein Kinase Inhibitors chemical synthesis
Receptor, trkA antagonists & inhibitors
Receptor, trkB antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 216
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33652352
- Full Text :
- https://doi.org/10.1016/j.ejmech.2021.113265