Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells
Curation statements for this article:-
Curated by eLife
Evaluation Summary:
This paper will be of broad interest to many fields, including drug discovery, cancer biology, and structure biology. It makes a significant advance in understanding the mechanism of action of hormone therapies for breast cancer, and how resistance driving mutations alter drug responses. The structural biology data has clear potential for strong impact though some additional analysis might be needed.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
Abstract
Chemical manipulation of estrogen receptor alpha ligand binding domain structural mobility tunes receptor lifetime and influences breast cancer therapeutic activities. Selective estrogen receptor modulators (SERMs) extend estrogen receptor alpha (ERα) cellular lifetime/accumulation. They are antagonists in the breast but agonists in the uterine epithelium and/or in bone. Selective estrogen receptor degraders/downregulators (SERDs) reduce ERα cellular lifetime/accumulation and are pure antagonists. Activating somatic ESR1 mutations Y537S and D538G enable resistance to first-line endocrine therapies. SERDs have shown significant activities in ESR1 mutant setting while few SERMs have been studied. To understand whether chemical manipulation of ERα cellular lifetime and accumulation influences antagonistic activity, we studied a series of methylpyrollidine lasofoxifene (Laso) derivatives that maintained the drug’s antagonistic activities while uniquely tuning ERα cellular accumulation. These molecules were examined alongside a panel of antiestrogens in live cell assays of ERα cellular accumulation, lifetime, SUMOylation, and transcriptional antagonism. High-resolution x-ray crystal structures of WT and Y537S ERα ligand binding domain in complex with the methylated Laso derivatives or representative SERMs and SERDs show that molecules that favor a highly buried helix 12 antagonist conformation achieve the greatest transcriptional suppression activities in breast cancer cells harboring WT/Y537S ESR1 . Together these results show that chemical reduction of ERα cellular lifetime is not necessarily the most crucial parameter for transcriptional antagonism in ESR1 mutated breast cancer cells. Importantly, our studies show how small chemical differences within a scaffold series can provide compounds with similar antagonistic activities, but with greatly different effects of the cellular lifetime of the ERα, which is crucial for achieving desired SERM or SERD profiles.
Article activity feed
-
-
Evaluation Summary:
This paper will be of broad interest to many fields, including drug discovery, cancer biology, and structure biology. It makes a significant advance in understanding the mechanism of action of hormone therapies for breast cancer, and how resistance driving mutations alter drug responses. The structural biology data has clear potential for strong impact though some additional analysis might be needed.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
-
Reviewer #1 (Public Review):
This is an impressive structural and molecular mechanistic study in the modes of action of a series of SERMs / SERDs. Such large scale comparative studies on ligands binding to ER (or proteins in general) and of great value to the field as these studies greatly surpass studies on isolated singular examples in terms of impact and relevance. It is in the comparison of a large set of compounds that trends and design principles can be extracted.
Also of high relevance is the study of these SERMs/SERDs in the context of the resistance acquiring ER537/538 mutations. Molecular understanding of the underlying mechanisms is lacking here and the authors make a valuable contribution.
The data on the pyrrolidine methyl-substituted Lasofoxifenes are fascinating. -
Reviewer #2 (Public Review):
Fanning and Greene present an important addition to the idea that one of the two major classes of ER antagonists, selective estrogen receptor degraders (SERDs), do not require degradation for efficacy. They used a chemical biology approach to develop derivatives of lasofoxifene analogs that have a single methyl group added and identified isomers that either stabilize or destabilize the receptor. They profiled these compounds and a panel of clinical and preclinical antagonists for effects on receptor levels, post-translational modifications, coactivator recruitment, transcriptional activity and proliferation. They generated two major conclusions: degradation does not correlate with efficacy; and that the patterns of pharmacology across the panel of ligands are markedly different in the WT ER or in two …
Reviewer #2 (Public Review):
Fanning and Greene present an important addition to the idea that one of the two major classes of ER antagonists, selective estrogen receptor degraders (SERDs), do not require degradation for efficacy. They used a chemical biology approach to develop derivatives of lasofoxifene analogs that have a single methyl group added and identified isomers that either stabilize or destabilize the receptor. They profiled these compounds and a panel of clinical and preclinical antagonists for effects on receptor levels, post-translational modifications, coactivator recruitment, transcriptional activity and proliferation. They generated two major conclusions: degradation does not correlate with efficacy; and that the patterns of pharmacology across the panel of ligands are markedly different in the WT ER or in two constitutive mutants that drive metastatic disease and treatment resistance. They presented a series of crystal structures with 8 ligands bound to the WT or Y537S ER. A more careful interpretation of these structures might be needed to make conclusions regarding the structural basis of efficacy, but the structures are of high interest in revealing how the Y537S mutant changes how the ligands interact with the receptor to drive differences in pharmacology from the WT receptor.
-
