التفاصيل البيبلوغرافية
| العنوان: |
Development of Potent Dual BET/HDAC Inhibitors via Pharmacophore Merging and Structure-Guided Optimization |
| المؤلفون: |
Nicolas Bauer, Dimitrios-Ilias Balourdas, Joel R. Schneider, Xin Zhang, Lena M. Berger, Benedict-Tilman Berger, Martin P. Schwalm, Nick A. Klopp, Jens T. Siveke, Stefan Knapp, Andreas C. Joerger |
| سنة النشر: |
2024 |
| المجموعة: |
Smithsonian Institution: Figshare |
| مصطلحات موضوعية: |
Biochemistry, Molecular Biology, Pharmacology, Cancer, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, target activity translated, nut midline carcinoma, future translational studies, could also show, choosing starting scaffolds, 100 nm range, guided optimization bromodomain, different cancer models, pancreatic cancer cells, potent dual bet, available dual bet, 50 , pancreatic cancer, dual bet, guided modification, cancer therapy, tp63 <, p57 <, myc <, hexim1 <, bet inhibition, two functionalities, tumor suppressor, treat tumors |
| الوصف: |
Bromodomain and extra-terminal domain (BET) proteins and histone deacetylases (HDACs) are prime targets in cancer therapy. Recent research has particularly focused on the development of dual BET/HDAC inhibitors for hard-to-treat tumors, such as pancreatic cancer. Here, we developed a new series of potent dual BET/HDAC inhibitors by choosing starting scaffolds that enabled us to optimally merge the two functionalities into a single compound. Systematic structure-guided modification of both warheads then led to optimized binders that were superior in potency to both parent compounds, with the best molecules of this series binding to both BRD4 bromodomains as well as HDAC1/2 with EC 50 values in the 100 nM range in cellular NanoBRET target engagement assays. For one of our lead molecules, we could also show the selective inhibition of HDAC1/2 over all other zinc-dependent HDACs. Importantly, this on-target activity translated into promising efficacy in pancreatic cancer and NUT midline carcinoma cells. Our lead molecules effectively blocked histone H3 deacetylation in pancreatic cancer cells and upregulated the tumor suppressor HEXIM1 and proapoptotic p57 , both markers of BET inhibition. In addition, they have the potential to downregulate the oncogenic drivers of NUT midline carcinoma, as demonstrated for MYC and TP63 mRNA levels. Overall, this study expands the portfolio of available dual BET/class I HDAC inhibitors for future translational studies in different cancer models. |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
unknown |
| العلاقة: |
https://figshare.com/articles/journal_contribution/Development_of_Potent_Dual_BET_HDAC_Inhibitors_via_Pharmacophore_Merging_and_Structure-Guided_Optimization/25117159Test |
| DOI: |
10.1021/acschembio.3c00427.s001 |
| الإتاحة: |
https://doi.org/10.1021/acschembio.3c00427.s001Test |
| حقوق: |
CC BY-NC 4.0 |
| رقم الانضمام: |
edsbas.34CF5A05 |
| قاعدة البيانات: |
BASE |
