PROTAC-mediated degradation of class I histone deacetylase enzymes in corepressor complexes.

We have identified a proteolysis targeting chimera (PROTAC) of class I HDACs 1, 2 and 3. The most active degrader consists of a benzamide HDAC inhibitor, an alkyl linker, and the von Hippel-Lindau E3 ligand. Our PROTAC increased histone acetylation levels and compromised colon cancer HCT116 cell viability, establishing a degradation strategy as an alternative to class I HDAC inhibition.

[1]  P. Cole,et al.  Mechanism of Crosstalk between the LSD1 Demethylase and HDAC1 Deacetylase in the CoREST Complex , 2020, Cell reports.

[2]  C. Crews,et al.  Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery , 2020, Cell.

[3]  M. Rots,et al.  The timeline of epigenetic drug discovery: from reality to dreams , 2019, Clinical Epigenetics.

[4]  Weiping Tang,et al.  Development of Multi-Functional Histone Deacetylase 6 Degraders with Potent Anti-Myeloma Activity. , 2019, Journal of medicinal chemistry.

[5]  C. Crews,et al.  PROteolysis TArgeting Chimeras (PROTACs) - Past, present and future. , 2019, Drug discovery today. Technologies.

[6]  C. Crews,et al.  Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase , 2019, Nature Communications.

[7]  Wei Wu,et al.  Developing potent PROTACs tools for selective degradation of HDAC6 protein , 2019, Protein & Cell.

[8]  T. Yamashita,et al.  Class I histone deacetylase (HDAC) inhibitor CI-994 promotes functional recovery following spinal cord injury , 2018, Cell Death & Disease.

[9]  Xiao Wang,et al.  H3K9ac and HDAC2 Activity Are Involved in the Expression of Monocarboxylate Transporter 1 in Oligodendrocyte , 2017, Front. Mol. Neurosci..

[10]  C. Crews,et al.  Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead. , 2017, Cell chemical biology.

[11]  A. Ciulli,et al.  Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders , 2017, Essays in biochemistry.

[12]  Tudor I. Oprea.  Faculty Opinions recommendation of Structural basis of PROTAC cooperative recognition for selective protein degradation. , 2017 .

[13]  J. Schwabe,et al.  Targeting Class I Histone Deacetylases in a "Complex" Environment. , 2017, Trends in pharmacological sciences.

[14]  S. Houser,et al.  Class I Histone Deacetylase Inhibition for the Treatment of Sustained Atrial Fibrillation , 2016, The Journal of Pharmacology and Experimental Therapeutics.

[15]  Eunhwa Ko,et al.  Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL. , 2016, Angewandte Chemie.

[16]  Somy Yoon,et al.  HDAC and HDAC Inhibitor: From Cancer to Cardiovascular Diseases , 2016, Chonnam medical journal.

[17]  A. Ciulli,et al.  Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4 , 2015, ACS chemical biology.

[18]  Malini Guha.  HDAC inhibitors still need a home run, despite recent approval , 2015, Nature Reviews Drug Discovery.

[19]  R. Johnstone,et al.  Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders , 2014, Nature Reviews Drug Discovery.

[20]  S. Hiebert,et al.  Class I HDACs Affect DNA Replication, Repair, and Chromatin Structure: Implications for Cancer Therapy. , 2014, Antioxidants & redox signaling.

[21]  O. Dovey,et al.  Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells , 2014, Proceedings of the National Academy of Sciences.

[22]  E. Seto,et al.  Erasers of histone acetylation: the histone deacetylase enzymes. , 2014, Cold Spring Harbor perspectives in biology.

[23]  Adam W. Bero,et al.  Epigenetic Priming of Memory Updating during Reconsolidation to Attenuate Remote Fear Memories , 2014, Cell.

[24]  Benjamin E. L. Lauffer,et al.  Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability , 2013, The Journal of Biological Chemistry.

[25]  S. Cowley,et al.  The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts. , 2013, Biochemical Society transactions.

[26]  E. Choi,et al.  Impact of linker length on the activity of PROTACs. , 2011, Molecular bioSystems.

[27]  J. Nakayama,et al.  Physiological Roles of Class I HDAC Complex and Histone Demethylase , 2010, Journal of biomedicine & biotechnology.

[28]  O. Dovey,et al.  Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation , 2010, Proceedings of the National Academy of Sciences.

[29]  W. Weichert.  HDAC expression and clinical prognosis in human malignancies. , 2009, Cancer letters.

[30]  T. Beckers,et al.  Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group , 2007, International journal of cancer.

[31]  P. LoRusso,et al.  Preclinical antitumor activity of CI-994 , 2004, Investigational New Drugs.