Recent progress in selective estrogen receptor downregulators (SERDs) for the treatment of breast cancer

Abstract

Selective estrogen receptor downregulators (SERDs) are a novel class of compounds capable of reducing the ERα protein level and blocking ER activity. Therefore, SERDs are considered as a significant therapeutic approach to treat ER+ breast cancer in both early stage and more advanced drug-resistant cases. After the FDA approval of a steroidal drug, fulvestrant, as a SERD for the treatment of breast cancer in patients who have progressed on antihormonal agents, several molecules with diverse chemical structures have been rapidly developed, studied and evaluated for selective estrogen receptor downregulation activity. Here we compile the promising SERDs reported in recent years and discuss the chemical structure and pharmacological profile of the most potent compound of the considered series. Because of the availability of only a limited number of effective drugs for the treatment of breast cancer, the quest for a potent SERD with respectable activity and bioavailability is still ongoing. The goal of this article is to make available to the reader an overview of the current progress in SERDs and provide clues for the future discovery and development of novel pharmacological potent SERDs for the treatment of breast cancer.

Fig. 1. Chemical structure of FDA-approved drugs (1–4) for the treatment of breast cancer.

Fig. 2. Chemical structure of compounds (5–10) in clinical trials for the treatment of breast cancer.

Fig. 3. Chemical structure of ICI 164384 (11) and steroidal derivatives 12–14.

Fig. 4. Chemical structure of triaryl ethylene derivatives 15–17.

Fig. 5. Chemical structure of raloxifene (18), arzoxifene (19) and benzothiophene derivatives 20–24.

Fig. 6. Chemical structure of SS5020 (25), SS1020 (26), 7-hydroxy quinoline derivatives (27 and 28), coumarin derivatives (29 and 30), EM 652 (31) and chromene derivatives (32–34).

Fig. 7. Chemical structure of benzoxepin derivatives 35–37.

Fig. 8. Chemical structure of tetrahydroisoquinoline derivatives 38–42.

Fig. 9. Chemical structure of tricyclic indazole derivative 43.

Fig. 10. Chemical structure of diphenyl alkane derivatives 44 and 45.

Fig. 11. Chemical structure of cyclofenil (46), bicyclononane (47) and adamantyl analogues 48 and 49.

Fig. 12. Chemical structure of oxabicycloheptene sulfonamides 50–52.