Balanced dual acting compounds targeting aromatase and estrogen receptor α as an emerging therapeutic opportunity to counteract estrogen responsive breast cancer
| Autor: | Matic Pavlin, Jessica Caciolla, Eleonora Turrini, Nadia Zaffaroni, Alessandra Magistrato, Alessandra Bisi, Carmela Fimognari, Silvia Martini, Angelo Spinello, Federica Simonelli, Federica Belluti, Angela Rampa, Silvia Gobbi |
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| Přispěvatelé: | Caciolla J., Martini S., Spinello A., Pavlin M., Turrini E., Simonelli F., Belluti F., Rampa A., Bisi A., Fimognari C., Zaffaroni N., Gobbi S., Magistrato A. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Molecular dynamic
Antineoplastic Agents Hormonal medicine.drug_class In silico Estrogen receptor Breast Neoplasms Molecular dynamics QM/MM Breast cancer breast cancer Drug Discovery medicine Humans Aromatase IC50 Pharmacology chemistry.chemical_classification biology Aromatase Inhibitors Multitarget Organic Chemistry Estrogen Antagonists Aromatase inhibitor General Medicine medicine.disease SERM Enzyme chemistry Estrogen Cell culture Settore CHIM/03 - Chimica Generale E Inorganica SERD biology.protein Cancer research Female |
| Popis: | Breast Cancer (BC) is a leading cause of death in women, currently affecting 13% of female population worldwide. First-line clinical treatments against Estrogen Receptor positive (ER+) BC rely on suppressing estrogen production, by inhibiting the aromatase (AR) enzyme, or on blocking estrogen-dependent pro-oncogenic signaling, by targeting Estrogen Receptor (ER) α with selective Modulators/Degraders (SERMs/SERDs). The development of dual acting molecules targeting AR and ERα represents a tantalizing alternative strategy to fight ER + BC, reducing the incidence of adverse effects and resistance onset that limit the effectiveness of these gold-standard therapies. Here, in silico design, synthesis, biological evaluation and an atomic-level characterization of the binding and inhibition mechanism of twelve structurally related drug-candidates enable the discovery of multiple compounds active on both AR and ERα in the sub-μM range. The best drug-candidate 3a displayed a balanced low-nanomolar IC50 towards the two targets, SERM activity and moderate selectivity towards a BC cell line. Moreover, most of the studied compounds reduced ERα levels, suggesting a potential SERD activity. This study dissects the key structural traits needed to obtain optimal dual acting drug-candidates, showing that multitarget compounds may be a viable therapeutic option to counteract ER + BC. |
| Databáze: | OpenAIRE |
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