2. Academic Validation
  3. Discovery of pyrazolo-thieno[3,2-d]pyrimidinylamino-phenyl acetamides as type-II pan-tropomyosin receptor kinase (TRK) inhibitors: Design, synthesis, and biological evaluation

Discovery of pyrazolo-thieno[3,2-d]pyrimidinylamino-phenyl acetamides as type-II pan-tropomyosin receptor kinase (TRK) inhibitors: Design, synthesis, and biological evaluation

  • Eur J Med Chem. 2021 Apr 15:216:113265. doi: 10.1016/j.ejmech.2021.113265.
Wei Yan 1,  Lingtian Zhang 1,  Fengping Lv 1,  Marialuisa Moccia 2,  Francesca Carlomagno 3,  Christophe Landry 4,  Massimo Santoro 2,  Fabien Gosselet 4,  Brendan Frett 1,  Hong-Yu Li 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
  • 2 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II, Via S Pansini 5, 80131, Naples, Italy.
  • 3 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II, Via S Pansini 5, 80131, Naples, Italy; Istituto di Endocrinologia e Oncologia Sperimentale Del CNR, Via S Pansini 5, 80131, Naples, Italy.
  • 4 Blood Brain Barrier Laboratory (LBHE), University of Artois, UR2465, F-62300, Lens, France.
  • 5 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. Electronic address: HLi2@uams.edu.
PMID: 33652352 DOI: 10.1016/j.ejmech.2021.113265
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.

Keywords

Colorectal cancer; Kinase inhibitor; TRK; Type-II.

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