Mechanism-based discovery of SERMs and SERDs
Until relatively recently it was considered that there were two ways to inhibit estrogen action in Estrogen Receptor (ER) positive breast tumors, (a) competitively block the binding of endogenous agonists (estrogens) with “antiestrogens” or (b) limit the production of “estrogens” using aromatase inhibitors. However, in work focused on the development of tissue selective estrogens for the prevention/treatment of osteoporosis, we made the observation that different ER ligands acting through the same receptor could induce different transcriptional/functional responses in cells [1]. Exploring the molecular basis for this observation, we developed the concept of “functional allostery”, which posits that the conformation of ER is influenced by the structure of the ligand with which it binds and that the shape of the ER-ligand complex predicts pharmacological activity. We showed that “shape matters” as it enables the receptor to interact in a differential manner with functionally distinct coregulators resulting in different pharmacological responses [2].
Early studies that exploited the concept of functional allostery led to the development of the Selective Estrogen Receptor Modulators (SERMs) lasofoxifene and bazedoxifene, both of which are now in clinical trials for breast cancer. Later work led to the identification of DPC974 (now called etacsil), which has a dramatic effect on the structure of the carboxyl-terminus of ERα, triggering its ubiquitination and subsequent proteasome-dependent degradation [3-5]. DPC974 was a first-in-class oral Selective Estrogen Receptor Downregulator (SERD). In collaboration with DuPont/BMS, this drug was evaluated in a phase I/IIa clinical trial where considerable efficacy was observed in patients with endocrine therapy resistant disease. Whereas development of this drug was discontinued for non-scientific reasons, we and others have capitalized on the mechanistic insights from this work to identify additional SERDs, several of which are currently in clinical development (see table below). Exploiting the concept of functional allostery we discovered that RAD1901 (Elacestrant, Orserdu™), a drug which failed in clinical trials for hot flashes, was in fact a SERD that functioned in a manner that was different from all other drugs in this class [6]. We (Duke) licensed the enabling intellectual property, describing the repurposing of this drug to Radius Health (Boston) who developed it as a breast cancer therapeutic. Building on very positive activity in early clinical studies, a registration trial was initiated (EMERALD: NCT03778931). This trial achieved both of its primary endpoints and the drug was approved by the FDA (US) in January 2023 and the EMEA (Europe) in September 2023. This was the first new endocrine therapy approved in 20 years.
Our recent work on the molecular pharmacology of ESR1 mutants led to the rediscovery of the SERM lasofoxifene (Fablyn™) as a breast cancer therapeutic [7]. The enabling intellectual property was licensed by Duke to Sermonix and this drug is now in Phase III clinical trial(s) (ELAINE: NCT03781063).
Our continued work in this area is exploring new chemical scaffolds upon which to build new classes of ER modulators [8, 9]. We also have an interest in defining the specific coregulators that are utilized by ER in regulating different aspects of ER biology and with this knowledge we believe that it will be possible to prospectively identify process selective ER modulators.
Conflict of interest statement: Duke University has and may continue to receive income from Radius Health and Sermonix from licensing of intellectual property covering the use of elacestrant and lasofoxifene for use in cancer (license fees, milestones, royalties, and equity). In accordance with the Duke revenue sharing policy members of the McDonnell laboratory stand to benefit financially.
Key References
1. McDonnell, D.P., et al., Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol Endocrinol, 1995. 9(6): p. 659-69.
2. Norris, J.D., et al., Peptide antagonists of the human estrogen receptor. Science, 1999. 285(5428): p. 744-6.
3. Connor, C.E., et al., Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor. Cancer Res, 2001. 61(7): p. 2917-22.
4. Wijayaratne, A.L., et al., Comparative analyses of mechanistic differences among antiestrogens. Endocrinology, 1999. 140(12): p. 5828-40.
5. Wu, Y.L., et al., Structural basis for an unexpected mode of SERM-mediated ER antagonism. Mol Cell, 2005. 18(4): p. 413-24.
6. Wardell, S.E., et al., Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader. Endocr Relat Cancer, 2015. 22(5): p. 713-24.
7. Andreano, K.J., et al., The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor. Mol Cancer Ther, 2020. 19(7): p. 1395-1405.
8. Reddy Sammeta, V., et al., Structural Determinants of the Binding and Activation of Estrogen Receptor α by Phenolic Thieno[2,3-d]pyrimidines. Helvetica Chimica Acta. e202300097.
9. Sammeta, V.R., et al., A New Chemotype of Chemically Tractable Nonsteroidal Estrogens Based on a Thieno[2,3-d]pyrimidine Core. ACS Medicinal Chemistry Letters, 2022. 13(7): p. 1151-1158.
