Title

Synthesis, Characterization and Molecular Docking Studies of Derivatives of HDAC Inhibitors

Poster Number

9C

Lead Author Affiliation

Chemical Synthesis, Drug Discovery and Design

Lead Author Status

Doctoral Student

Second Author Affiliation

Chemical Synthesis, Drug Discovery and Design

Second Author Status

Masters Student

Introduction

HAT (histone acetyltransferase) and HDAC (histone deacetylase) are two key enzymes in epigenetic control. They collaborate to acetylate and deacetylate histone lysine residues, resulting in either a more relaxed or compacted chromatin structure (1,2). In some cancers, HDAC enzymes have been found to be overexpressed leading to chromatin condensation (3, 4, 5). HDACs are the enzymes responsible for the removal of an acetyl group from the lysine residue of the histone protein, therefore causing the DNA to wrap around the histones more tightly. Such modifications are associated with gene silencing, which are significant for healthy cell division (6, 7, 8). In cancers where HDACs are overexpressed, platinum anticancer drugs cannot attack DNA by the formation of cross-links, thus can no longer prevent DNA transcription from occurring. To combat tightly wrapped DNA and promote more relaxed chromatin structures, HDAC inhibitors (HDACi) are used in clinical treatment of cancers (9).

We are focusing on the synthesis of five different HDACi derivatives: D01, D03, D16, D17, and D19, all of which are derivatives of Vorinostat and Panobinostat. Simultaneously, molecular docking studies to compare their binding affinities and inhibition constants to that of the clinically approved drugs were conducted.

Purpose

Our goal is to synthesize, purify, and analyze derivatives of Vorinostat and Panobinostat, and incorporate them into Pt drug derivatives to produce Pt-HDACi bifunctional drug candidates. Combining regular chemotherapeutic medications such as Pt drugs with low doses of HDACis is a promising way to improve efficacy for this class of drugs. Our aim is to hybridize these two classes of drug which hopefully allow for a more selective and less toxic form of drug therapy.

Method

HDACi derivatives were designed by changing the zinc-binding group on suberoylanilide hydroxamic acid (SAHA) and Panobinostat. After synthesizing the analogs, they were purified and characterized. NMR spectroscopy and Mass spectrometry were performed to ensure composition and purity of the products. The possible HDACi derivatives were also evaluated by molecular docking using Autodock Vina to assess binding affinity with the hydrophobic pocket located near the zinc-binding domain of the HDAC enzymes.

Results

D01, D03, D16, D17, and D19 derivatives were synthesized, purified, and isolated under normal wet lab conditions. D01, a derivative of Vorinostat, has less binding affinity for human HDAC1 than Vorinostat. On the other hand, derivative of Panobinostat, D19 has demonstrated better binding affinity for human HDAC1 than Panobinostat. Thus, D19 will be a good candidate with platinum core to form the bifunctional Pt drugs. D03, D16, and D17 have yet to be tested for binding affinity.

Significance

HDAC inhibitors have made it into the list of FDA approved drugs as effective agents in cancer treatment. However, these anticancer agents are associated with toxicities such as neutropenia, thrombocytopenia, fatigue, anemia, and diarrhea. Some instances of deaths were reported in clinical trials involving suberoylanilide hydroxamic acid (SAHA) or Vorinostat (10). These side effects could be due to the lack of selectivity and low binding affinity towards HDAC enzymes. Selectivity of HDACi can be improved by modifying the structures, to target the newly discovered hydrophobic region on HDAC enzymes. This will lead to higher binding affinities and an increase in binding duration thereby enhancing the potency of the drug with reduced toxicity. Our group also asks the question, when Pt drug and HDACi derivatives that have different mechanisms of action are co-hybridized, what may be the benefits associated with such a strategy. Main aims of the project are to address the question of whether these co-hybridized Pt-HDAC derivatives will have better efficacy over combination therapy, and how tuning of the HDACi derivatives could enhance the bioactivities of the bifunctional drug candidates.

Location

William Knox Holt Memorial Library and Learning Center, University of the Pacific, 3601 Pacific Ave., Stockton, CA 95211

Format

Poster Presentation

Poster Session

Morning

This document is currently not available here.

Share

COinS
 
Apr 30th, 10:00 AM Apr 30th, 12:00 PM

Synthesis, Characterization and Molecular Docking Studies of Derivatives of HDAC Inhibitors

William Knox Holt Memorial Library and Learning Center, University of the Pacific, 3601 Pacific Ave., Stockton, CA 95211

HAT (histone acetyltransferase) and HDAC (histone deacetylase) are two key enzymes in epigenetic control. They collaborate to acetylate and deacetylate histone lysine residues, resulting in either a more relaxed or compacted chromatin structure (1,2). In some cancers, HDAC enzymes have been found to be overexpressed leading to chromatin condensation (3, 4, 5). HDACs are the enzymes responsible for the removal of an acetyl group from the lysine residue of the histone protein, therefore causing the DNA to wrap around the histones more tightly. Such modifications are associated with gene silencing, which are significant for healthy cell division (6, 7, 8). In cancers where HDACs are overexpressed, platinum anticancer drugs cannot attack DNA by the formation of cross-links, thus can no longer prevent DNA transcription from occurring. To combat tightly wrapped DNA and promote more relaxed chromatin structures, HDAC inhibitors (HDACi) are used in clinical treatment of cancers (9).

We are focusing on the synthesis of five different HDACi derivatives: D01, D03, D16, D17, and D19, all of which are derivatives of Vorinostat and Panobinostat. Simultaneously, molecular docking studies to compare their binding affinities and inhibition constants to that of the clinically approved drugs were conducted.