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

ABSTRACT: Resistance to endocrine therapies remains a major clinical problem for the treatment of estrogen receptor-? (ER?)-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 ER? 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 ER?-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.

SUBMITTER: Srinivasan S 

PROVIDER: S-EPMC5161551 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature