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  2. Chemo-proteomics exploration of HDAC degradability by small molecule degraders

Chemo-proteomics exploration of HDAC degradability by small molecule degraders

  • Cell Chem Biol. 2021 Oct 21;28(10):1514-1527.e4. doi: 10.1016/j.chembiol.2021.07.002.
Yuan Xiong 1 Katherine A Donovan 1 Nicholas A Eleuteri 2 Nadia Kirmani 2 Hong Yue 1 Anthony Razov 2 Noah M Krupnick 2 Radosław P Nowak 1 Eric S Fischer 3
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
Abstract

Targeted protein degradation refers to the use of small molecules that recruit a ubiquitin ligase to a target protein for ubiquitination and subsequent proteasome-dependent degradation. While degraders have been developed for many targets, key questions regarding degrader development and the consequences of acute pharmacological degradation remain, specifically for targets that exist in obligate multi-protein complexes. Here, we synthesize a pan-histone deacetylase (HDAC) degrader library for the chemo-proteomic exploration of acute degradation of a key class of chromatin-modifying enzymes. Using chemo-proteomics, we not only map the degradability of the zinc-dependent HDAC family identifying leads for targeting HDACs 1-8 and 10 but also explore important aspects of degrading epigenetic enzymes. We discover cell line-driven target specificity and that HDAC degradation often results in collateral loss of HDAC-containing repressive complexes. These findings potentially offer a new mechanism toward controlling chromatin structure, and our resource will facilitate accelerated degrader design and development for HDACs.

Keywords

E3 ligase; HDAC; IMiD; PROTAC; collateral degradation; degrader; targeted degradation; ubiquitin.

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