Full antagonism of the estrogen receptor without a prototypical ligand side chain

Abstract

Resistance to endocrine therapies remains a significant clinical problem for estrogen receptor-α (ERα)-positive breast cancer. On-target side effects limit therapeutic compliance and use for chemoprevention, highlighting an unmet need for new therapies. Here we present a full-antagonist ligand series lacking the prototypical ligand side chain that has been universally used to engender antagonism of ERα through poorly understood structural mechanisms. A series of crystal structures and phenotypic assays reveal a structure-based design strategy with separate design elements for antagonism and degradation of the receptor and access to a structurally distinct space for further improvements in ligand design. Understanding structural rules that guide ligands to produce diverse ERα-mediated phenotypes has broad implications for the treatment of breast cancer and other estrogen-sensitive aspects of human health including bone homeostasis, energy metabolism, and autoimmunity.

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

“…Other side chain design strategies could be evaluated, as could the optimal matching between antiestrogen side chains and core structural elements, with the goal of optimizing affinity, potency, and antiproliferative efficacy, while also seeking the best pharmacokinetic behavior. There are even alternative approaches to disrupting the ERα agonist conformation by indirect mechanisms using ligands with expanded core elements (even ones without side chains) that distort the positioning of regions within the ligand-binding pocket that are needed to support the agonist conformation of helix 12 50,101–103 . Finally, it will also be important to clarify the necessity—or even the desirability—of coupling ERα antagonism with ERα degradation (SERD activity), and determine whether ERα levels of both WT and mutant ERs can be lowered sufficiently to afford broad suppression of breast cancer progression.…”

Exploring the Structural Compliancy versus Specificity of the Estrogen Receptor Using Isomeric Three-Dimensional Ligands

“…11 A third series with a sulfonamide linker (OBHS-N) enabled attachment of two pendent groups, some of which reached a full antagonist profile comparable to fulvestrant on the wild type receptor. 11, 14 …”

Dual mechanism estrogen receptor inhibitors

“…We found that certain ER antagonist ligands operate by a second mechanism called "indirect antagonism" 6,13 . This occurs when ligands with bulky cores perturb secondary structural elements within the ligand binding pocket (LBP), typically by shifting the C-terminal end of h11; this movement acts indirectly through the h11-h12 loop to regulate the dynamics of h12 and can be used to fully control the conformational ensemble of the receptor between active and repressive states 14,15 .…”

“…1ac). [3][4][5][6] Both SERMs and full antagonists have a common ligand structural feature, namely, a ligand core onto which is attached a single pendant side chain that requires very precise interaction with the receptor to control the degree of antagonism. These include aminoalkoxy groups exemplified in various SERMs (tamoxifen, raloxifene, bazedoxifene and lasofoxifene) that interact with the receptor with a single H-bond to stabilize the position of the side chain ( Supplementary Fig.…”