Trapoxin A Analogue as a Selective Nanomolar Inhibitor of HDAC11

Authors

Thanh Tu Ho, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
Changmin Peng, Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, George Washington Cancer Center, George Washington University, Washington, District of Columbia 20037, United States.
Edward Seto, Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, George Washington Cancer Center, George Washington University, Washington, District of Columbia 20037, United States.
Hening Lin, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.

Document Type

Journal Article

Publication Date

3-28-2023

Journal

ACS chemical biology

DOI

10.1021/acschembio.2c00840

Abstract

Histone deacetylases (HDACs) are enzymes that regulate many important biological pathways. There is a need for the development of isoform-selective HDAC inhibitors for further biological applications. Here, we report the development of trapoxin A analogues as potent and selective inhibitors of HDAC11, an enzyme that can efficiently remove long-chain fatty acyl groups from proteins. In particular, we show that one of the trapoxin A analogues, TD034, has nanomolar potency in enzymatic assays. We show that in cells, TD034 is active at low micromolar concentrations and inhibits the defatty acylation of SHMT2, a known HDAC11 substrate. The high potency and selectivity of TD034 would permit further development of HDAC11 inhibitors for biological and therapeutic applications.

APA Citation

Ho, Thanh Tu; Peng, Changmin; Seto, Edward; and Lin, Hening, "Trapoxin A Analogue as a Selective Nanomolar Inhibitor of HDAC11" (2023). GW Authored Works. Paper 2531.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/2531

Department

Biochemistry and Molecular Medicine