Introduction: Estrogen receptor-positive (ER+) breast cancer is the most common subtype of breast cancer worldwide. Estrogens, after being synthetized by aromatase, bind to ERα promoting breast cancer proliferation (1). Therefore, the therapies already approved act either by inhibiting aromatase or by modulating ERα. However, besides their therapeutic success, they induce several side effects (2), reason why it is crucial to discover novel therapeutic approaches.
Aim: Considering that aromatase activity and ERα activation display important roles in this type of cancer, our goal is to discover multi-target compounds able to simultaneously inhibit aromatase and modulate ERα.
Methods: We used the ChEMBL Database to retrieve all the known aromatase inhibitors (AIs) and ERα antagonists. Using the ChemAxon software we computed two types of chemical descriptors: extended connectivity fingerprints and the pharmacophore fingerprints of each compound. After this, clusters were constructed and the selected compounds were analyzed by molecular docking. Anti-aromatase activity was evaluated in human placental microsomes and ERα expression was assessed by Western-Blot in ER+ an aromatase-overexpressing breast cancer cell line (MCF-7aro).
Results: Based on clusters and after docking studies one compound (MT1) was selected to be studied in microsomes and in MCF-7aro cells. Although MT1 binds to key residues in aromatase important for its inhibition, unexpectedly, MT1 was not able to inhibit this enzyme in microsomes. However, as Exemestane, the steroidal AI used in clinic (1), MT1 induced a decrease in aromatase protein levels in MCF-7aro cells. Furthermore, MT1 impaired ERα activation, acting as an ERα antagonist.
Discussion: To the best of our knowledge, this is the first attempt to discover multi-target compounds for ER+ breast cancer, using this type of approach. In fact, the compound MT1 was able to modulate aromatase and ERα, two key targets of this type of cancer, which represents a great advantage over other molecules used in breast cancer treatment.
Acknowledgments: The authors are grateful to Fundação para a Ciência e Tecnologia (FCT) for CA Post-doc grant (SFRH/BPD/98304/2013) and for the financial support (UID/MULTI/04378/2019).
- Amaral C, Varela CL, Mauricio J, Sobral AF, Costa SC, Roleira FMF, et al. Anti-tumor efficacy of new 7alpha-substituted androstanes as aromatase inhibitors in hormone-sensitive and resistant breast cancer cells. J Steroid Biochem Mol Biol. 2017;171:218-28.
2. Augusto TV, Correia-da-Silva G, Rodrigues CMP, Teixeira N, Amaral C. Acquired resistance to aromatase inhibitors: where we stand! Endocr Relat Cancer. 2018;25(5):R283-R301.