Design and Synthesis of Novel Epigenetic Inhibitors Targeting Histone Deacetylases, DNA Methyltransferase 1, and Lysine Methyltransferase G9a with In Vivo Efficacy in Multiple Myeloma
| Autor: | Elena Sáez, Musheng Xu, Raquel Ordoñez, Amaia Vilas-Zornoza, Feifei Zhang, Xabier Agirre, Antonio Pineda-Lucena, Obdulia Rabal, Julen Oyarzabal, Felipe Prosper, Edurne San José-Enériz, Estíbaliz Miranda, Irene de Miguel, Leire Garate, Juan A. Sánchez-Arias, Ander Estella, Wei Wu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
Methyltransferase biology Chemistry 01 natural sciences DNA methyltransferase 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences chemistry.chemical_compound Histone In vivo Drug Discovery biology.protein Cancer research Molecular Medicine Gene silencing Epigenetics Gene DNA 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 64:3392-3426 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c02255 |
| Popis: | Concomitant inhibition of key epigenetic pathways involved in silencing tumor suppressor genes has been recognized as a promising strategy for cancer therapy. Herein, we report a first-in-class series of quinoline-based analogues that simultaneously inhibit histone deacetylases (from a low nanomolar range) and DNA methyltransferase-1 (from a mid-nanomolar range, IC50 1 log unit), and a suitable pharmacokinetic profile. In vivo, 12a achieved significant antitumor efficacy in a xenograft mouse model of human multiple myeloma. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|