Development of Potent Dual BET/HDAC Inhibitors via Pharmacophore Merging and Structure-Guided Optimization
Nicolas Bauer1,2, Dimitrios-Ilias Balourdas1,2, Joel R Schneider3,4
1Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
Abstract:
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 EC50 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.
Insights
Researchers developed novel dual Bromodomain and extra-terminal domain (BET) and histone deacetylase (HDAC) inhibitors for difficult cancers. These potent compounds show promise in pancreatic and NUT midline carcinoma models by targeting key cancer-driving genes.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Molecular Pharmacology
Background:
- Bromodomain and extra-terminal domain (BET) proteins and histone deacetylases (HDACs) are validated targets in oncology.
- Developing dual inhibitors offers a strategy for hard-to-treat cancers like pancreatic cancer.
Purpose of the Study:
- To design and synthesize novel dual BET/HDAC inhibitors.
- To optimize these inhibitors for enhanced potency and selectivity against cancer cells.
Main Methods:
- Structure-guided design and systematic modification of inhibitor scaffolds.
- Cellular NanoBRET target engagement assays to determine binding affinities (EC50).
- Assessment of target engagement and downstream effects in cancer cell lines.
Main Results:
- Developed potent dual BET/HDAC inhibitors with EC50 values in the 100 nM range for BRD4 and HDAC1/2.
- Identified a lead molecule selectively inhibiting HDAC1/2 over other HDACs.
- Demonstrated efficacy in pancreatic and NUT midline carcinoma models, including modulation of key cancer markers (H3 acetylation, HEXIM1, p57, MYC, TP63).
Conclusions:
- The study presents a new series of potent dual BET/class I HDAC inhibitors.
- These compounds exhibit promising anti-cancer activity in preclinical models.
- The findings support further translational studies for these novel inhibitors.
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