Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design
| العنوان: | Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design |
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| المؤلفون: | Ching Kim Tye, Chunhong Yan, Sarah C. Traeger, Wayne Vaccaro, Yingru Zhang, Gerry Everlof, Jianqing Li, Henry Yip, Peng Li, John T. Hunt, Michael A. Poss, Gregory D. Vite, Mussari Christopher P, Steven Sheriff, Asoka Ranasinghe, Haiying Zhang, Richard A. Westhouse, Dharmpal S. Dodd, Richard Rampulla, Zheng Yang, Frank Marsilio, Derek J. Norris, Wen-Ching Han, Tram N. Huynh, Yufen Zhao, Patrice Gill, Nirmala Raghavan, Lalgudi S. Harikrishnan, Ashvinikumar V. Gavai, Susan Wee, John S. Tokarski, Dauh-Rurng Wu, Arvind Mathur, Mei-Li Wen, Huiping Zhang, David R. Tortolani, George V. Delucca, Krista Menard, Francis Y. Lee, Claude A. Quesnelle, Dawn Sun, Vijay T. Ahuja, Daniel O'malley, Christine Huang, Muthoni G. Kamau |
| المصدر: | Journal of Medicinal Chemistry. 64:14247-14265 |
| بيانات النشر: | American Chemical Society (ACS), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Drug, Proline, Phenylalanine, media_common.quotation_subject, Carbazoles, Administration, Oral, Antineoplastic Agents, Cell Cycle Proteins, Computational biology, BET inhibitor, Structure-Activity Relationship, Pharmacokinetics, In vivo, Drug Discovery, Transcriptional regulation, Humans, Potency, media_common, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Tryptophan, Signal transducing adaptor protein, Bromodomain, Molecular Medicine, Transcription Factors |
| الوصف: | Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e6552024d7da4fe4ccaa968fbe1cf079 https://doi.org/10.1021/acs.jmedchem.1c00625 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....e6552024d7da4fe4ccaa968fbe1cf079 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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