posted on 2020-03-18, 15:03authored byKa Yang, Hao Wu, Zhongrui Zhang, Eric D. Leisten, Xueqing Nie, Binkai Liu, Zhi Wen, Jing Zhang, Michael D. Cunningham, Weiping Tang
Histone deacetylase 6 (HDAC6) is
involved in multiple cellular
processes such as aggresome formation, protein stability, and cell
motility. Numerous HDAC6-selective inhibitors have been developed
as cellular chemical tools to elucidate the function of HDAC6. Since
HDAC6 has multiple domains that cannot be studied by HDAC6-selective
inhibitors, CRISPR-CAS9 and siRNA/shRNA have been employed to elucidate
the nonenzymatic functions of HDAC6. However, these genetic methods
have many limitations. Proteolysis targeting chimera (PROTAC) is an
emerging technology for the development of small molecules that can
quickly remove the entire protein in cells. We previously developed
multifunctional HDAC6 degraders that can recruit cereblon (CRBN) E3
ubiquitin ligase. These HDAC6 degraders can degrade not only HDAC6
but also neo-substrates of CRBN. They are excellent candidates for
the development of anticancer therapeutics, but the multifunctional
nature of the CRBN-based HDAC6 degraders has limited their utility
as specific chemical probes for the study of HDAC6-related cellular
pathways. Herein we report the development of the first cell-permeable
HDAC6-selective degraders employing Von Hippel–Lindau (VHL)
E3 ubiquitin ligase, which does not have any known neo-substrates.
The DC50’s of the most potent compound 3j are 7.1 nM and 4.3 nM in human MM1S and mouse 4935 cell lines, respectively.
The Dmax’s of 3j in
these two cell lines are 90% and 57%, respectively.