2. Academic Validation
  3. Development of Potent Dual BET/HDAC Inhibitors via Pharmacophore Merging and Structure-Guided Optimization

Development of Potent Dual BET/HDAC Inhibitors via Pharmacophore Merging and Structure-Guided Optimization

  • ACS Chem Biol. 2024 Feb 16;19(2):266-279. doi: 10.1021/acschembio.3c00427.
Nicolas Bauer 1 2,  Dimitrios-Ilias Balourdas 1 2,  Joel R Schneider 3 4,  Xin Zhang 3 4,  Lena M Berger 1 2,  Benedict-Tilman Berger 1 2,  Martin P Schwalm 1 2 5,  Nick A Klopp 3 4,  Jens T Siveke 3 4,  Stefan Knapp 1 2 5,  Andreas C Joerger 1 2
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 2 Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
  • 3 Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
  • 4 Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK Partner Site Essen) and German Cancer Research Center, DKFZ, 69120 Heidelberg, Germany.
  • 5 German Translational Cancer Network (DKTK) Site Frankfurt/Mainz, Frankfurt am Main 60438, Germany.
PMID: 38291964 DOI: 10.1021/acschembio.3c00427
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.

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