La Monica Gabriele, Alamia Federica, Bono Alessia, Mingoia Francesco, Martorana Annamaria, Lauria Antonino
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche "STEBICEF", University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy.
Istituto per lo Studio dei Materiali Nanostrutturati, Consiglio Nazionale delle Ricerche (CNR), 90128 Palermo, Italy.
Molecules. 2024 Dec 21;29(24):6040. doi: 10.3390/molecules29246040.
Breast cancer remains one of the most prevalent and lethal malignancies in women, particularly the estrogen receptor-positive (ER+) subtype, which accounts for approximately 70% of cases. Traditional endocrine therapies, including aromatase inhibitors, selective estrogen receptor degraders/antagonists (SERDs), and selective estrogen receptor modulators (SERMs), have improved outcomes for metastatic ER+ breast cancer. However, resistance to these agents presents a significant challenge. This study explores a novel therapeutic strategy involving the simultaneous inhibition of the estrogen receptor (ER) and the chaperone protein Hsp90, which is crucial for the stabilization of various oncoproteins, including ER itself. We employed a hybrid, hierarchical in silico virtual screening approach to identify new dual ER/Hsp90 inhibitors, utilizing the Biotarget Predictor Tool (BPT) for efficient multitarget screening of a large compound library. Subsequent structure-based studies, including molecular docking analyses, were conducted to further evaluate the interaction of the top candidates with both ER and Hsp90. Supporting this, molecular dynamics simulations demonstrate the high stability of the multitarget inhibitor in complex with ER and Hsp90. Our findings suggest that several small molecules, particularly compound , exhibit promising potential as dual inhibitors, representing a new avenue to overcome resistance in ER+ breast cancer.
乳腺癌仍然是女性中最常见和致命的恶性肿瘤之一，尤其是雌激素受体阳性（ER+）亚型，约占病例的70%。传统的内分泌疗法，包括芳香化酶抑制剂、选择性雌激素受体降解剂/拮抗剂（SERD）和选择性雌激素受体调节剂（SERM），改善了转移性ER+乳腺癌的治疗效果。然而，对这些药物的耐药性构成了重大挑战。本研究探索了一种新的治疗策略，即同时抑制雌激素受体（ER）和伴侣蛋白Hsp90，Hsp90对包括ER自身在内的多种癌蛋白的稳定至关重要。我们采用了一种混合的、分层的计算机虚拟筛选方法来识别新的ER/Hsp90双重抑制剂，利用生物靶点预测工具（BPT）对大型化合物库进行高效的多靶点筛选。随后进行了基于结构的研究，包括分子对接分析，以进一步评估顶级候选物与ER和Hsp90的相互作用。分子动力学模拟表明，多靶点抑制剂与ER和Hsp90形成的复合物具有很高的稳定性，支持了这一结论。我们的研究结果表明，几种小分子，特别是化合物，作为双重抑制剂具有很有前景的潜力，代表了克服ER+乳腺癌耐药性的新途径。
