kunsel Lecture 22: Epigenetic Therapies-HDAC Inhibitors

histone structural motifs for epigenetic signaling

• protein methylation

• acetylation

• phosphorylation

histone structural motifs for epigenetic signaling

• protein methylation

• acetylation

• phosphorylation

• CpG island shore & CpG island ~ methylation

• lysine ~ acetylation

• phosphorylation?

HATs

enzyme that puts acetyl groups onto histone & other proteins

HDACs

catalyze acetyl group removal from histones & other proteins

HDAC inhibitors

vorinostat

romidepsin

what drug

vorinostat (SAHA) strucuture

romidepsin (FK-228) structure

romidepsin prodrug mechanism

disulfide reduction

what makes romidepsin (FK-228) a prodrug?

disulfide bond → reduction activation

HDAC inhibitor structural motif

metal chelating ligand → reacts with Zn2+ on HDACi

why is epigenetic drug development so complicated?

HAT & HDAC proteins target other things besides histone proteins

tripartite motif of HDAC inhibitors