Development of subtype class I-selective histone deacetylase inhibitors and degraders for reversing and prevention of therapy resistance in cancer

• Applicants: Professor Dr. Finn Kristian Hansen; Professor Dr. Matthias Kassack
• Subject Area: Pharmacy
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 496726881

Epigenetic disturbance is a major contributor to tumorigenesis, tumor progression and the development of chemoresistance. Histone deacetylases (HDACs) have emerged as validated drug targets, particularly in hematological malignancies. In solid cancers, HDAC inhibitors (HDACi) in combination with established anti-cancer drugs (e.g. platinum drugs, kinase inhibitors) have shown promising effects mostly in preclinical studies. FDA- or EMA-approved HDACi are pan-HDACi and exhibit a certain selectivity towards cancer cells vs. non-cancer cells, however, a plethora of serious side effects has been reported. Therefore, several strategies are currently under investigation to retain anti-cancer effects and reduce potential side effects: development of class- or subtype-selective HDACi; development of HDACi-based dual-target drugs; and development of HDAC degraders (PROTACs). Whereas selective HDAC6 inhibitors (e.g. tubastatin A) or class I-selective HDACi (e.g. entinostat) are available, HDACi highly selective within class I, i.e. inhibitors of HDAC1, HDAC2, or HDAC3 are mostly not available. In previous collaboration projects between our research groups, we have discovered a preferential HDAC1 inhibitor and an HDAC3 preferential inhibitor bearing aminoanilide-based zinc-binding groups and capable of fully reversing chemoresistance in a cellular model of platinum resistance. Further, a novel resin-based synthesis method has been developed and resulted in dual-targeting HDACi-alkylating agents acting synergistically. Based on these promising results, we have the overall objective to develop class I isoform selective HDACi, class I HDAC degraders, and dual-targeting nitrogen mustard-HDACi hybrid molecules for reversal and prevention of chemoresistance. Class I isoform selective HDACi and degraders will allow us to explore the contribution of each respective class I HDAC isoform to the chemosensitivity of cancer cells. Since chemoresistance is often associated with increased kinase signaling, combination treatments of HDACi or degraders with kinase inhibitors will be investigated next to established cytostatic agents. Knock-out studies of class I HDACs, performed in the lab of our collaborator Prof. Hanenberg, will complement the pharmacological inhibition of HDACs. Whereas chemical synthesis and HDAC enzyme assays will be performed in the Hansen lab, cellular assays such as cytotoxicity, synergy, apoptosis, DNA damage, degradation of HDACs and HDAC protein complexes by HDAC-PROTACs will be analyzed in the Kassack lab. RNA-seq expression data will be acquired in the presence of the most promising class I-selective HDACi and degrader and in the knock-out clones to elucidate the (patho)biological contribution of class I HDACs and the most potent class I-selective HDACi from this study. Finally, the top scoring compounds will be examined in the chorion allantois membrane (CAM) in vivo model established in the lab of our collaboration partner.

• DFG Programme: Research Grants