De Filippis Barbara, Agamennone Mariangela, Ammazzalorso Alessandra, Amoroso Rosa, Giampietro Letizia, Maccallini Cristina, Sağlık Begüm Nurpelin, De Simone Chiara, Zuccarini Mariachiara, Kaplancıklı Zafer Asım, Fantacuzzi Marialuigia
Department of Pharmacy, University "G. D'Annunzio" of Chieti-Pescara, 66100 Chieti, Italy.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey.
Pharmaceuticals (Basel). 2025 Aug 15;18(8):1206. doi: 10.3390/ph18081206.
Third-generation aromatase inhibitors (CYP19A1) are the mainstay of treatment for estrogen-receptor-positive breast cancer. This is because estrogen is required for cancer growth in approximately 70% of patients with this condition. Although potent and effective, aromatase inhibitors induce resistance and secondary effects, requiring treatment to be discontinued. This clinical limitation highlights the need to search for new molecules. Previous studies have led to the identification of a set of indole sulfonamide molecules that exhibit interesting activity against aromatase. Phenyl and benzyl sulfonamide derivatives with alkylated heterocycles linked by short methylene bridges were designed and synthesized. The aromatase inhibition and cytotoxicity were tested through in vitro assays. Molecular docking and dynamic simulations evaluated the interactions with the aromatase enzyme, while a target fishing strategy linked to gene associations relevant to breast cancer helped to uncover other targets. All of the non-steroidal inhibitors synthesized showed significant activity. Compounds and demonstrated IC values in the low micromolar range and selective action against MCF7 breast cancer cells over healthy lines. Computational studies confirmed stable and favorable aromatase binding. Target fishing identified EGFR and PTK2B as additional potential targets for a multi-target therapeutic strategy. Compounds and outperform indole-based inhibitors in their potency and selectivity, revealing strong therapeutic potential. Their binding affinity and specificity support further development. EGFR and PTK2B may enable a broader, multi-target approach.
第三代芳香化酶抑制剂（CYP19A1）是雌激素受体阳性乳腺癌治疗的主要手段。这是因为在大约70%的此类患者中，雌激素是癌症生长所必需的。尽管芳香化酶抑制剂强效且有效，但会诱导耐药性和产生副作用，导致治疗不得不中断。这一临床局限性凸显了寻找新分子的必要性。先前的研究已鉴定出一组对芳香化酶具有有趣活性的吲哚磺酰胺分子。设计并合成了具有通过短亚甲基桥连接的烷基化杂环的苯基和苄基磺酰胺衍生物。通过体外试验测试了芳香化酶抑制作用和细胞毒性。分子对接和动力学模拟评估了与芳香化酶的相互作用，而与乳腺癌相关基因关联的靶标垂钓策略有助于发现其他靶点。所有合成的非甾体抑制剂均显示出显著活性。化合物 和 表现出低微摩尔范围的IC值以及对MCF7乳腺癌细胞相对于健康细胞系的选择性作用。计算研究证实了与芳香化酶的稳定且有利的结合。靶标垂钓确定表皮生长因子受体（EGFR）和蛋白酪氨酸激酶2B（PTK2B）为多靶点治疗策略的其他潜在靶点。化合物 和 在效力和选择性方面优于基于吲哚的抑制剂，显示出强大的治疗潜力。它们的结合亲和力和特异性支持进一步开发。EGFR和PTK2B可能促成更广泛的多靶点方法。
