Grytsai Oleksandr, Dufies Maeva, Le Du Julie, Rastoin Olivia, Pires Gonçalves Leticia Christina, Mateo Lou, Lacas-Gervais Sandra, Cao Yihai, Demange Luc, Pagès Gilles, Benhida Rachid, Ronco Cyril
Université Côte d'Azur, CNRS UMR 7272, Institut de Chimie de Nice, 06108 Nice, France.
Roca Therapeutics, 27 Rue du Professeur Delvalle, 06000 Nice, France.
ACS Med Chem Lett. 2024 Apr 3;15(6):845-856. doi: 10.1021/acsmedchemlett.4c00053. eCollection 2024 Jun 13.
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 ,'-diarylurea analogues as ELRCXCL-CXCR1/2 inhibitors. Evaluations on RCC and HNSCC cell lines and 3D spheroid cultures identified compound 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. studies on zebrafish embryos and RCC xenografted mice showed notable anticancer, antimetastatic, and antiangiogenic effects after oral administration and minimal toxicity. Compound emerges as a promising candidate for further preclinical development as an oral anticancer and antiangiogenic drug targeting the ELRCXCL-CXCR1/2 pathway.
CXCR1/2生物分子在癌细胞增殖、肿瘤炎症和血管生成中发挥着至关重要的作用，这使其成为有吸引力的药物靶点。在透明细胞肾细胞癌（RCC）和头颈部鳞状细胞癌（HNSCC）中，CXCR1/2呈过度表达，但针对其的抑制研究却很有限。基于之前的研究成果，我们研究了新型的,'-二芳基脲类似物作为ELRCXCL-CXCR1/2抑制剂。对RCC和HNSCC细胞系以及3D球体培养物的评估确定化合物为先导分子，对侵袭、迁移和新血管生成表现出显著抑制作用。它对信号通路表现出强烈干扰，对激酶具有高选择性。对斑马鱼胚胎和RCC异种移植小鼠的研究表明，口服给药后具有显著的抗癌、抗转移和抗血管生成作用，且毒性极小。化合物成为一种有前景的候选物，可作为针对ELRCXCL-CXCR1/2途径的口服抗癌和抗血管生成药物进行进一步的临床前开发。
