P2: Solid-phase synthesis of selective histone deacetylase degraders

In preliminary work, the Hansen group has developed an efficient solid-phase synthesis of histone deacetylase (HDAC) degraders (PROTACs). The concept relies on the immobilization of the HDAC ligand on a solid support.

For the synthesis of the desired HDAC PROTACs, iterative cycles of Fmoc deprotection and amide coupling reactions were performed to introduce the HDAC cap, the PROTAC linker, and the ubiquitin E3 ligase ligand in a modular fashion. The prototypic PROTAC was inspired by the unselective HDAC inhibitor vorinostat and demonstrated unselective HDAC degradation.

The aim of this project is to utilize this solid-phase protocol for the preparation of HDAC degrader libraries that are capable of degrading HDAC6 and class IIa HDACs in a selective manner. For the development of selective HDAC6 degraders, the vorinostat-like HDAC ligand will be replaced by selective HDAC6 ligands.

In accordance with recently published selective class IIa HDAC inhibitors, benzhydryl hydroxamic acids will be used as HDAC ligands to engage the ‘lower selectivity pocket’ of class IIa isoforms. The synthesized HDAC PROTACs will be examined on the biochemical, cell biological, and mechanistic level to investigate their inhibition and degradation of HDACs.

The evaluation of the degradation efficiency of the synthesized PROTACs will be performed in close collaboration with P5. Improved E3 ligase ligands developed in P1 will be utilized to optimize the HDAC degraders.