دورية أكاديمية
Bispecific Estrogen Receptor α Degraders Incorporating Novel Binders Identified Using DNA-Encoded Chemical Library Screening.
| العنوان: | Bispecific Estrogen Receptor α Degraders Incorporating Novel Binders Identified Using DNA-Encoded Chemical Library Screening. |
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| المؤلفون: | Disch JS; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Duffy JM; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Lee ECY; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Gikunju D; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Chan B; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Levin B; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Monteiro MI; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Talcott SA; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Lau AC; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Zhou F; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Kozhushnyan A; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Westlund NE; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Mullins PB; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Yu Y; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., von Rechenberg M; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Zhang J; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Arnautova YA; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Liu Y; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Zhang Y; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., McRiner AJ; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Keefe AD; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Kohlmann A; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Clark MA; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Cuozzo JW; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Huguet C; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Arora S; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2021 Apr 22; Vol. 64 (8), pp. 5049-5066. Date of Electronic Publication: 2021 Apr 12. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | DNA/*chemistry , Estrogen Receptor alpha/*metabolism , Small Molecule Libraries/*chemistry, Animals ; Breast Neoplasms/drug therapy ; Cell Line, Tumor ; Cell Survival/drug effects ; Click Chemistry ; DNA/metabolism ; Estrogen Antagonists/chemistry ; Estrogen Antagonists/metabolism ; Estrogen Antagonists/pharmacology ; Estrogen Antagonists/therapeutic use ; Estrogen Receptor alpha/chemistry ; Estrogen Receptor alpha/genetics ; Female ; Half-Life ; Humans ; Indoles/chemistry ; Indoles/metabolism ; Kinetics ; Mice ; Small Molecule Libraries/metabolism ; Small Molecule Libraries/pharmacology ; Small Molecule Libraries/therapeutic use ; Structure-Activity Relationship ; Xenograft Model Antitumor Assays |
| مستخلص: | Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening ∼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplar 7 exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant of 7 rapidly generated bispecific nanomolar degraders of ERα, with PROTACs 18 and 21 inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization. |
| المشرفين على المادة: | 0 (Estrogen Antagonists) 0 (Estrogen Receptor alpha) 0 (Indoles) 0 (Small Molecule Libraries) 9007-49-2 (DNA) Q16TT9C5BK (bazedoxifene) |
| تواريخ الأحداث: | Date Created: 20210412 Date Completed: 20210614 Latest Revision: 20210614 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1021/acs.jmedchem.1c00127 |
| PMID: | 33844532 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.1c00127 |