期刊
NATURE CHEMICAL BIOLOGY
卷 13, 期 1, 页码 111-118出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.2236
关键词
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资金
- National Institutes of Health [PHS 5R37DK015556, 5R33CA132022, 5R0IDK077085, 1U01GM102148, 5R01CA130932]
- Breast Cancer Research Foundation
- BallenIsles Men's Golf Association
- Frenchman's Creek Women for Cancer Research
- Susan G. Komen for the Cure [PDF12229484]
- National Natural Science Foundation of China [81172935, 81373255, 81573279]
- Hubei Province's Outstanding Medical Academic Leader Program
- US Department of Energy Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences (NIGMS) [P41GM103393]
- NATIONAL CANCER INSTITUTE [R01CA200669, R33CA132022, R01CA130932] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK015556, R01DK077085, R37DK015556] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P41GM103393, U01GM102148] Funding Source: NIH RePORTER
Resistance to endocrine therapies remains a major clinical problem for the treatment of estrogen receptor-alpha (ER alpha)-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 alpha 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 alpha-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.
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