HDACs: Active drug targets for Immunotherapy treatment

For many pathologies such as cancer or neurological disorders, it has been found that Histone Deacetylase (HDAC) activity is disrupted, making them promising targets for drug development. Scientists need access to a broade range of products ( Active Enzyme, inhibitors/activators, Biochemical screening assays…), to simplify their research and identification of HDAC inhibitors.

Fig 1. Histone Deacetylases (HDAC) activity for down regulation of gene expression

HDACs currently represent the most well studied family of Deacetylases. By removing acetyl groups they will induce compaction of the heterochromatin conformation, and thereby negatively regulating gene expression.

It has been shown that HDAC activity is often disrupted in cancer (1) and neurological disorders (2), and therefore, HDACs have become an active drug target for the treatment of these pathologies. Several HDAC inhibitors have received FDA approval as anti-cancer drugs, and dozens more are in clinical trials.

Combined effect of HDAC inhibitors and anti PD-1 treatment

Fig 2.Model of mechanism of synergy between HDACi and anti-PD-1 treatment
(A) HDACi induce T cell chemokine expression.(B) When treated with PD-1 blockade and HDACi, anti-PD-1 enhances IFNγ expression in T cells and tumor cells become more responsive to IFNγ through HDACi mediated effects.(C) Finally, both anti-PD-1 and HDACi may directly and synergistically enhance T cell function.

Previous studies (1) have shown that Romidepsin, a FDA approved HDAC inhibitor (HDACi) can enhance the effect of PD-1 immunotherapy treatment. By inhibiting the HDAC activity, this inhibitor increased expression of multiple T cell chemokines attracting genes (Ccl5, Cxcl9 and Cxc10) in cancer cells, macrophages and T cells. In vivo an increase of chemokine expression, an enhancement of T cell infiltration and also a T cell-dependant tumour regression have been observed. As shown in fig. 2, the Romidepsin enhanced the response of PD-1 blockade immunotherapy in multiple lung tumour models, including nearly complete rejection in two models.

By showing a combined effect with PD-1 blockade immunotherapy, this result provides evidence of the role of HDACs in the induction T cell chemokine expression and provides a new approach to improve Immunotherapy treatment by combining existing treatments and new HDAC inhibitors.

A full offer for all your HDACs research

To help you in your daily work and also to simplify your research on HDAC proteins, tebu-bio brings you the full offer of products, making it more easy for researchers across Europe to obtain more accurate data.

HDAC Fluorogenic Assay Kit

This HDAC Fluorogenic assay allows easy screening and selection of new hits, increasing or blocking HDAC activity.

This method (fig 3.) eliminates dealing with the radioactivity, extraction, and chromatography aspects of other assays, and require only three simple steps:

Fig 3. HDAC-fluoregenic-assay-principle

 

  1. Incubate the HDAC fluorometric subtrate with purified HDAC enzyme.
  2. Add the HDAC developer for the fluorogenic production
  3. Read samples in a microtiter plate-reading fluorimeter

 

In the HDAC assay, fluorescent-dye molecules are attached to a peptide containing acetyl-lysine. Attachment to the peptide quenches the fluorescence of the dye. After treatment of the peptide with a HDAC, the reaction is mixed with a development solution that is specific for non-acetylated lysines. If the acetyl group has been removed from the lysine by the HDAC, this solution will release the dye allowing for fluorescence. Fluorescence is therefore directly related to HDAC activity.

HDAC purified enzymes and chemical compounds

Fig 4. Four classes of HDAC enzymes
Classes I, II, IV: Classic HDAC enzymes
Class III: Sirtuin enzymes (requires NAD+ cofactor for their activity)

In addition to this screening assay, BPS Biosciences was the first company to offer a full suite of active HDAC and Sirtuin proteins, enabling you to work on the four classes of HDAC enzymes (Fig 4.)

 

To complete this already quite full offer, tebu-bio also provides a number of HDAC inhibitors/activators and substrates for all of the HDAC classes.

 

Don’t hesitate to contact your tebu-bio local office to get more information and facilitate your HDAC inhibitor screening.

References:

  1. Zheng H. et al. 2016. HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma. Clin Cancer Res. 2016 Aug 15;22(16):4119-32
  2. Jia H. et al. 2015. HDAC inhibition imparts beneficial transgenerational effects in Huntington’s disease mice via altered DNA and histone methylation. Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):E56-64
Frédéric Samazan
Written by Frédéric Samazan
Frédéric Samazan is a Product Manager at tebu-bio, and an avid football fan in his spare time.