Development of carborane-based selective histone deacetylase inhibitors

• Applicants: Professor Dr. Finn Kristian Hansen; Professorin Dr. Evamarie Hey-Hawkins
• Subject Area: Pharmacy ; Inorganic Molecular Chemistry - Synthesis and Characterisation ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 512342974

The elevated expression of histone deacetylases (HDACs) in various tumor types renders their inhibition an attractive strategy for epigenetic therapeutics. One key issue in the development of improved HDAC inhibitors (HDACi) is the design of isoform-selective HDACi rather than unspecific pan-inhibitors in order to minimize off-target toxicity. HDACi can be characterized by a sophisticated pharmacophore model: a typical HDACi comprises a hydrophobic cap group, an aliphatic or aromatic linker chain, and a zinc-binding group (ZBG). This concept afforded numerous highly potent HDACi, including the FDA-approved drugs panobinostat, belinostat, and vorinostat. To further improve the membrane permeability, selectivity, and potency of this almost exclusively carbon-based scaffold, our research groups have started a close cooperation in which we recently accomplished the successful implementation of inorganic boron clusters (carboranes) as three-dimensional bioisosteres. The synthesis of HDACi featuring stable polyhedral boranes was achieved using a highly versatile and straightforward solid-phase protocol that afforded a small library of potent compounds whose isoform selectivity profiles could be steered through only minor structural changes. Encouraged by those results, we recognized the necessity to further investigate this sector of medicinal chemistry and decided to expand the compound library toward four selectivity branches: to begin with, the biological potency of unselective HDACi will be optimized using alternative linkers and different carborane-based cap groups. Secondly, carborane-based cap groups will be tailored to match the spacious loop pockets of HDAC6 to achieve selective inhibition of this clinically preferred isoform. A third goal is the selective inhibition of HDAC1 and HDAC2 utilizing a ortho-aminoanilide ZBG. This modification or replacement aims to optimize the carborane derivatives in terms of their ability to engage the foot pockets of HDAC1 and HDAC2. The fourth and last branch of our selectivity map will feature carborane-based side chains designed to fit into the so-called lower pocket of class IIa HDACs. Upon successful synthesis, all resulting compounds will undergo extensive biochemical profiling. Fluorogenic assays will be used to assess the in vitro target inhibition and isoform selectivity of each compound; the antiproliferative activity against cancer cell lines will be evaluated in MTT or resazurin cell viability assays. Synergy experiments will be carried out to explore the potential of combinations of HDAC6i and proteasome inhibitors against multiple myeloma cells, whereas the ability to reverse cisplatin resistance will be tested using MTT assays at the cisplatin-resistant A2780CisR cell line. Further experiments will investigate the in vitro stability and physicochemical properties.

• DFG Programme: Research Grants