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-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-me

SUBMITTER: Srinivasan S 

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

REPOSITORIES: biostudies-literature