Mechanism of N-Acylthiourea-mediated Activation of Human Histone Deacetylase 8 (HDAC8) at Molecular and Cellular Levels

Abstract

Background: N-Acylthiourea (TM-2-51) is an HDAC8-selective activator. Results: TM-2-51 binds to HDAC8 at two sites in a positive cooperative manner, and it produces anticancer effect in neuroblastoma cells. Conclusion: TM-2-51 modulates the binding thermodynamics/kinetics of substrate/inhibitor to HDAC8, and it enhances the cellular expression of p53/p21. Significance: These mechanistic studies will shed light on designing HDAC-selective activators as potential therapeutic agents.

Real-time monitoring of conformational transitions of single-molecule histone deacetylase 8 with nanocircuits

“…20 The arithmetic average of overall turnover rates is in strong agreement with ensemble measurements, particularly the observation of the bound duration of the HDAC8–cSAHA complex. The agreement suggests that HDAC8 has two major different pre-existing conformations associated with the τ high and ${\mathit{\tau }}_{\text{high}}^{\text{long}}$, which significantly affects the stability of the complex conformation.…”

“…2d illustrates a control measurement from the same circuit performed in the presence of both HDAC8 and excess SAHA-inhibitors (30 μM) in the buffer solution. Since the freely-diffusive SAHA-inhibitors surrounding HDAC8 immediately bind to HDAC8 in the solution, no SAHA-free HDAC8 is accessible to the pSAHA-nanocircuit, 20 resulting in no Δ I ( t ) fluctuations. The absence of the two-level current fluctuation when no HDAC8 is in the solution or when both HDAC8 and excess SAHA-inhibitors are present confirms that Δ I ( t ) signals are caused by the HDAC8–pSAHA complex.…”

Biochemical and Structural Characterization of HDAC8 Mutants Associated with Cornelia de Lange Syndrome Spectrum Disorders

“…However, Srivastava and colleagues have utilized enzymological, biophysical, and molecular modeling approaches to understand the molecular basis of HDAC8 activation by TM251. 51 Interestingly, these investigators find that TM251 binds to HDAC8 at two sites in a cooperative manner; additionally, TM251 modestly enhances inhibitor binding affinity by approximately 2-fold. From analysis of the enzyme structure and molecular modeling of enzyme–activator complexes, these investigators conclude that TM251 binds near the active site, potentially stabilizing active site loops that are important for the binding of substrates and inhibitors.…”

Exifone is a Potent HDAC1 Activator with Neuroprotective Activity in Human Neuronal Models of Neurodegeneration

“…Defining targets regulating these mechanisms if of great interest from the perspective of gaining fundamental insight into nervous system function and potential therapeutic applications. In these contexts, activation of class I HDACs via small molecules has been the subject of only a limited amount of studies 4,[25][26] . With the initial discovery of the role of an increase of HDAC1 activity in the reduction of neurotoxicity due to aberrant activity of CDK5/p25 1 , our investigations have resulted in the identification of multiple smallmolecule HDAC1 activators 4,27 In particular, by pursuing the structure-activity relationship of a series of synthetic HDAC1 activators, exifone was identified as a potent activator of HDAC1 with nanomolar potency in RapidFire MS assays using acetylated substrates derived from both histone (H4K12Ac) and non-histone (p53K382Ac) sequences 27 .…”

“…Activation of another Class I HDAC8 has also been the subject of few investigations with the identification of N-acetylthiourea derivatives as highly potent and isozyme selective activators of HDAC8 26 . More significantly, HDAC8 activators may serve as possible leads in the therapeutic management of Cornelia de Lange Syndrome (CdLS) spectrum disorder [31][32] .…”