Development of BET inhibitors as potential treatments for cancer: A search for structural diversity
| Autor: | Chunhong Yan, Francis Y. Lee, Ashvinikumar V. Gavai, Melissa Kramer, Frank Marsilio, Eric Shields, Laura Monereau, Zuzana Haarhoff, Richard A. Westhouse, Lisa Zhang, Gerry Everlof, John S. Tokarski, Matthew D. Hill, Tatyana Zvyaga, Asoka Ranasinghe, Carolynn Fanslau, Ching Kim Tye, Steven Sheriff, Christine Huang, Andrew P. Degnan, Krista Menard, John Morrison, Haiquan Fang |
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| Rok vydání: | 2021 |
| Předmět: |
Clinical Biochemistry
Pharmaceutical Science Structural diversity Antineoplastic Agents Biochemistry BET inhibitor Mice Structure-Activity Relationship Drug Development Drug Discovery medicine Animals Humans Moiety Potency Mouse tumor Molecular Biology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Proteins Cancer Triazoles medicine.disease Combinatorial chemistry Bromodomain Molecular Medicine Multiple Myeloma Carbolines |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 44:128108 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2021.128108 |
| Popis: | We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 “cap” phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12, that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg. |
| Databáze: | OpenAIRE |
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