Synthesis of a HDAC inhibitor–nanogold probe for cryo-EM visualization in class I HDAC co-repressor complexes

• Wiktoria A. Pytel,
• John W. R. Schwabe and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2026, 22, 480–485, doi:10.3762/bjoc.22.35

• inhibitor CI-994, for cryo-electron microscopy (cryo-EM) visualization of the HDAC catalytic domain within class I HDAC co-repressor complexes. The nanogold probe retained HDAC inhibitory activity comparable to CI-994 against the HDAC1-LSD1-CoREST complex in vitro. In cryo-EM studies, 2D class averages

• domain within the CoREST complex. Keywords: CI-994; co-repressor complex; CoREST; cryo-EM; gold nanoparticle; HDAC; Introduction Histone deacetylase (HDAC) enzymes catalyze the hydrolysis of acetyl groups from N-acetylated lysine residues in histone proteins. HDACs are also capable of the deacetylation

• of the HDAC inhibitor–nanogold probe we utilized the class I HDAC inhibitor CI-994 (Figure 1). CI-994 is an inhibitor of HDAC1–3 and it inhibits HDAC1-CoREST-LSD1, HDAC2-CoREST-LSD1, and HDAC3-SMRT complex with IC50 values of 0.53 µM, 0.62 µM, and 0.14 µM, respectively [14][15]. Additionally, CI-994