A ‘click’ chemistry approach to novel entinostat (MS-275) based class I histone deacetylase proteolysis targeting chimeras
Jasmine M. Cross, Megan E. Coulson, Joshua P. Smalley, Wiktoria A. Pytel, Ozair Ismail, Justin S. Trory, Shaun M. Cowley, James T. Hodgkinson
Abstract
Click chemistry was utilised to prepare a library of PROTACs based on entinostat a class I histone deacetylase (HDAC) inhibitor in clinical trials. A novel PROTAC JMC-137 was identified as a HDAC1/2 and HDAC3 degrader in HCT116 cells. However, potency was compromised compared to previously identified class I HDAC PROTACs highlighting the importance in the choice of HDAC ligand, functional group for linker attachment and positioning in PROTAC design.
Topics & Concepts
Histone deacetylaseProteolysisClick chemistryHDAC11ChemistryComputational biologyHistoneHistone deacetylase 5Cell biologyBiologyBiochemistryCombinatorial chemistryGeneEnzymeProtein Degradation and InhibitorsHistone Deacetylase Inhibitors ResearchUbiquitin and proteasome pathways