التفاصيل البيبلوغرافية
| العنوان: |
Identification of Diarylurea Inhibitors of the Cardiac-Specific Kinase TNNI3K by Designing Selectivity Against VEGFR2, p38α, and B‑Raf |
| المؤلفون: |
Jaclyn R. Patterson (7011443), Alan P. Graves (1523860), Patrick Stoy (2698972), Mui Cheung (1523842), Tina A. Desai (11608852), Harvey Fries (1523845), Gregory J. Gatto (1523854), Dennis A. Holt (3024240), Lisa Shewchuk (1523839), Rachel Totoritis (1523827), Liping Wang (33601), Lara S. Kallander (1523863) |
| سنة النشر: |
1753 |
| المجموعة: |
Smithsonian Institution: Digital Repository |
| مصطلحات موضوعية: |
Biochemistry, Medicine, Cell Biology, Pharmacology, Biotechnology, Developmental Biology, Cancer, Inorganic Chemistry, Virology, Chemical Sciences not elsewhere classified, Information Systems not elsewhere classified, ray crystal structures, rat pharmacokinetic properties, discovering novel medicines, raf (> 200, reperfusion cardiac injury, promising kinase selectivity, 47 , b ‑ raf, specific kinase tnni3k, fold ), p38α, kinase selectivity, vivo <, gsk329 ), designing selectivity, therapeutic target, optimized exemplars, mouse model, favorable leads |
| الوصف: |
A series of diarylurea inhibitors of the cardiac-specific kinase TNNI3K were developed to elucidate the biological function of TNNI3K and evaluate TNNI3K as a therapeutic target for the treatment of cardiovascular diseases. Utilizing a structure-based design, enhancements in kinase selectivity were engineered into the series, capitalizing on the established X-ray crystal structures of TNNI3K, VEGFR2, p38α, and B-Raf. Our efforts culminated in the discovery of an in vivo tool compound 47 (GSK329), which exhibited desirable TNNI3K potency and rat pharmacokinetic properties as well as promising kinase selectivity against VEGFR2 (40-fold), p38α (80-fold), and B-Raf (>200-fold). Compound 47 demonstrated positive cardioprotective outcomes in a mouse model of ischemia/reperfusion cardiac injury, indicating that optimized exemplars from this series, such as 47 , are favorable leads for discovering novel medicines for cardiac diseases. |
| نوع الوثيقة: |
dataset |
| اللغة: |
unknown |
| العلاقة: |
https://figshare.com/articles/dataset/Identification_of_Diarylurea_Inhibitors_of_the_Cardiac-Specific_Kinase_TNNI3K_by_Designing_Selectivity_Against_VEGFR2_p38_and_B_Raf/16879387Test |
| DOI: |
10.1021/acs.jmedchem.1c00700.s002 |
| الإتاحة: |
https://doi.org/10.1021/acs.jmedchem.1c00700.s002Test |
| حقوق: |
CC BY-NC 4.0 |
| رقم الانضمام: |
edsbas.B8400779 |
| قاعدة البيانات: |
BASE |
