2. Academic Validation
  3. A Potent Solution for Tumor Growth and Angiogenesis Suppression via an ELR+CXCL-CXCR1/2 Pathway Inhibitor

A Potent Solution for Tumor Growth and Angiogenesis Suppression via an ELR+CXCL-CXCR1/2 Pathway Inhibitor

  • ACS Med Chem Lett. 2024 Apr 3;15(6):845-856. doi: 10.1021/acsmedchemlett.4c00053.
Oleksandr Grytsai 1,  Maeva Dufies 2 3,  Julie Le Du 1 2,  Olivia Rastoin 2,  Leticia Christina Pires Gonçalves 1 2,  Lou Mateo 1,  Sandra Lacas-Gervais 4,  Yihai Cao 5,  Luc Demange 1 6,  Gilles Pagès 2 3,  Rachid Benhida 1 2 7,  Cyril Ronco 1 2 8
Affiliations

Affiliations

  • 1 Université Côte d'Azur, CNRS UMR 7272, Institut de Chimie de Nice, 06108 Nice, France.
  • 2 Roca Therapeutics, 27 Rue du Professeur Delvalle, 06000 Nice, France.
  • 3 Université Côte d'Azur, CNRS UMR 7284 and INSERM U 1081, Institute for Research on Cancer and Aging (IRCAN), 28 Avenue de Valombrose, 06107 Nice, France.
  • 4 Université Côte d'Azur, CCMA, UAR Sciences, 06103 Nice, France.
  • 5 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
  • 6 Université de Paris, CiTCoM, UMR 8038 CNRS, F-75006 Paris, France.
  • 7 Mohamed VI Polytechnic University, UM6P, 43150 BenGuerir, Morocco.
  • 8 Institut Universitaire de France (IUF), 75005 Paris, France.
PMID: 38894897 DOI: 10.1021/acsmedchemlett.4c00053
Abstract

CXCR1/2 biomolecules play vital roles in Cancer cell proliferation, tumor inflammation, and angiogenesis, making them attractive drug targets. In clear cell renal cell carcinoma (RCC) and head and neck squamous cell carcinoma (HNSCC), where CXCR1/2 is overexpressed, inhibition studies are limited. Building upon previous research efforts, we investigated new N,N'-diarylurea analogues as ELR+CXCL-CXCR1/2 inhibitors. Evaluations on RCC and HNSCC cell lines and 3D spheroid cultures identified compound 10 as a lead molecule, exhibiting significant inhibition of invasion, migration, and neo-angiogenesis. It demonstrated strong interference with the signaling pathway, with high selectivity toward kinases. In vivo studies on zebrafish embryos and RCC xenografted mice showed notable Anticancer, antimetastatic, and antiangiogenic effects after oral administration and minimal toxicity. Compound 10 emerges as a promising candidate for further preclinical development as an oral Anticancer and antiangiogenic drug targeting the ELR+CXCL-CXCR1/2 pathway.

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