Elacestrant (RAD1901) is an Orally Available Estrogen Receptor Degrader

Breast cancer is subdivided into categories based on the tumor receptor status. Specifically, whether the tumor expresses estrogen receptor (ER), progesterone receptor (PR), or Her2. And, with ER⁺ disease makes up the majority of patients in the breast cancer patient population. Although there are currently available drugs against ER-positive breast cancers. However, many women eventually relapse with drug-resistant breast cancers. Estrogen and the estrogen receptor (ER) are prominent drivers of breast tumorigenesis and breast cancer progression. Therefore, we will introduce a novel, orally bioavailable, small-molecule selective estrogen receptor degrader-Elacestrant (RAD1901).

Elacestrant is an orally available selective estrogen receptor degrader (SERD) with IC₅₀s of 48 and 870 nM for ERα and ERβ, respectively.

In vitro, Elacestrant (0-1 µM; 24 or 48 h) results in a dose-dependent and marked decrease in estrogen receptor protein expression. In addition, Elacestrant (0.01, 0.1, 1.0 µM) decreases expression of progesterone receptor (PGR, PR; an ER target gene), in both MCF7 and T47D cells. Moreover, Elacestrant (0-1 µM; 48 h) inhibits proliferation of Estradiol (E2)-stimulated MCF-7 cells in a dose-dependent manner, with an EC₅₀ of 4 pM.

In addition, Elacestrant inhibits breast cancer cell proliferation in vivo. Elacestrant (30, 60 mg/kg; p.o.; single daily for 4 weeks) induces complete tumor growth inhibition in MCF7 cell line xenograft model of mice.  Interestingly, Elacestrant inhibits the growth of the tumor maintains for 4 weeks after withdrawal. In other words, Elacestrant can produce a stable and continued pharmacodynamic effect on ER signaling and sustained tumor growth inhibition across a range of doses.

Moreover, the combination of Elacestrant with either everolimus or palbociclib resulted in significantly greater tumor growth inhibition as compared with Elacestrant single-agent effects in mice.

To sum up, as a selective ER degrader, Elacestrant is a hopeful agent for breast cancer.

Reference:

1. Bihani T, et al. Clin Cancer Res. 2017 Aug 15;23(16):4793-4804. 
2. Garner F, et al. Anticancer Drugs. 2015 Oct;26(9):948-56.