posted on 2024-01-31, 08:43authored byNicolas 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
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.