Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure–Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1
| العنوان: | Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure–Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1 |
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| المؤلفون: | Kevin Ronald Condroski, Matt Hickman, Wei Liu, Laurie LeBrun, Gilles Carmel, Joshua Hansen, Gang Lu, Afshin Mahmoudi, Frans Baculi, Correa Matthew D, Tim Crea, Hon-Wah Man, George W. Muller, Chin-Chun Lu, Alexander L. Ruchelman, Fan Vocanson, Weihong Zhang |
| المصدر: | Journal of Medicinal Chemistry. 61:492-503 |
| بيانات النشر: | American Chemical Society (ACS), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Quantitative structure–activity relationship, biology, 010405 organic chemistry, Chemistry, Stereochemistry, Cereblon, Glutarimide, Protein degradation, 01 natural sciences, Molecular Docking Simulation, 0104 chemical sciences, Ubiquitin ligase, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, Biochemistry, Docking (molecular), Drug Discovery, biology.protein, Molecular Medicine, Ternary complex |
| الوصف: | We previously disclosed the identification of cereblon modulator 3 (CC-885), with potent antitumor activity mediated through the degradation of GSPT1. We describe herein the structure–activity relationships for analogs of 3 with exploration of the structurally related dioxoisoindoline class. The observed activity of protein degradation could in part be rationalized through docking into the previously disclosed 3–CRBN–GSPT1 cocrystal ternary complex. For SAR that could not be rationalized through the cocrystal complex, we sought to predict SAR through a QSAR model developed in house. Through these analyses, selective protein degradation could be achieved between the two proteins of interest, GSPT1 and Aiolos. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::82b447b68c060eec6fd08bffe825f2a7 https://doi.org/10.1021/acs.jmedchem.6b01911 |
| رقم الأكسشن: | edsair.doi...........82b447b68c060eec6fd08bffe825f2a7 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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