ADVERTISEMENT

Meta-Sulfamoyl N-Hydroxybenzamides As HDAC8-Selective Inhibitors

As a family of epigenetic enzymes, histone deacetylases (HDACs) can catalyze the removal of an acetyl group from N-acetyl lysine residues of histones and other proteins. The human HDACs can be grouped into 4 classes based on their homology to yeast prototypes: Class I (HDAC1, 2, 3 and 8), Class II (HDAC 4,5, 6, 7, 9 and 10) and Class IV (HDAC11) are zinc-dependent, while Class III (SIRT1-7) is NAD+-dependent.

HDAC8 is a unique zinc-dependent class I HDAC, identified as a 42 kDa protein composed of 377 amino acids and located in the nucleus and cytoplasm, where it plays numerous physiological and pathological roles. More importantly, there is increasing evidence showing that HDAC8 aberration contributes essentially to the onset and progression of many diseases, especially T-cell lymphoma, childhood neuroblastoma and Cornelia de Lange Syndrome (CdLS). Therefore, development of HDAC8 selective inhibitors is of great therapeutic value.

ADVERTISEMENT

In the present research, the knowledge-based rational design of HDAC inhibitor led to the discovery of three meta-sulfamoyl N-hydroxybenzamide-based HDAC8 selective inhibitors 12a-12c (Figure 1), which exhibited potent HDAC8 inhibition with two-digit nanomolar IC50 values, and remarkable selectivity over HDAC2 and HDAC6. Additionally, western blot analysis also supported such selectivity on the intracellular level.

Figure 1. Design of meta-sulfamoyl N-hydroxybenzamides-based HDAC8 inhibitors. Credit: Yingjie Zhang

It’s worth noting that compounds 12a-12c possessed selective cytotoxicity to T-cell leukemia cell lines Jurkat, Molt-4 and neuroblastoma cell line SK-N-BE-(2), which was also observed in the well-known HDAC8 selective inhibitor PCI-34051. The molecular docking study showed compounds 12a (Fig 2A), 12b (Fig 2B), 12c (Fig 2C), and PCI-34051(Fig 2D) shared a similar binding mode in the active site of HDAC8.

Figure 2. Proposed binding model of compounds 12a (cyans), 12b (yellow), 12c (green) and PCI-34051 (blue) with HDAC8 (PDB code: 2V5X). The zinc ion is shown as a red sphere. Hydrogen bonds and coordination of the zinc ion are shown as yellow dashed lines. Credit: Yingjie Zhang

In the past decades, several hundreds of clinical trials of more than 20 HDAC inhibitors, mainly as antitumor agents, have been initiated. However, most HDACIs in the clinic are pan-HDAC inhibitors or class selective inhibitors, which inhibit broad-spectrum HDACs and lead to nonnegligible toxicities. Therefore, development of HDAC inhibitors selective for a single isoform with the expectation of better tolerance and fewer side effects has become a hot topic. Though many HDAC8 selective inhibitors have been developed and exhibited satisfying toxic profiles, their in vitro and in vivo antitumor potency were not compelling enough for further clinical evaluation.

Two key points for the development of HDAC8-selective inhibitors are to find the accurate disease model and to get antitumor synergy in combination with other antitumor agents. For example, HDAC8 knockdown showed anti-proliferative activity in cells with a mutant, but not wild-type p53. Therefore, HDAC8 inhibitors might function as an adjuvant therapy for tumors with mutant p53.

ADVERTISEMENT

These results are vividly demonstrated in the article entitled Discovery of meta-sulfamoyl N-hydroxybenzamides as HDAC8 selective inhibitors, recently published in the European Journal of Medicinal Chemistry. This work was conducted by Chunlong Zhao, Jie Zang, Qin’ge Ding, Wenfang Xu, and Yingjie Zhang from the School of Pharmaceutical Sciences, Shandong University, and Elizabeth S. Inks and C. James Chou from South Carolina College of Pharmacy, Medical University of South Carolina.

Comments

READ THIS NEXT

What Is A Toadstool?

A toadstool, more commonly known as a mushroom, is the name given to the spore-bearing reproductive part of a fungus. The […]

Contributions Of Heat Pumps To Demand Response: A Case Study Of A Plus-Energy Dwelling

Electricity markets need to keep the balance between energy generation and energy consumption. Utility companies increasingly have to deal with […]

The Safety Of Final Repositories – Radiolytic Oxidation Reactions

Storage of spent nuclear fuel is a hot topic in many countries that are using or have used nuclear power […]

Conservative Ideology, Racial Resentment, & President Trump – An Interview With Dr. Hans Noel

At a time of political divisiveness and ideological battles, President Trump’s approval ratings have continued to decline since taking office. […]

Did Carbon Dioxide (CO2), Ocean Heat, Or Both Contribute To Global Warming During The Last 400,000 Years?

Published by Knut L. Seip, Øyvind Grøn and Hui Wang OsloMet – Oslo Metropolitan University and the NOAA/NWS/NCEP/Climate Prediction Center These […]

Large-Scale Farmland Investments And The Land-Water-Energy-Food Nexus

In response to energy policies and resource scarcity, many countries have become interested in finalizing farmland commercial agreements mainly with […]

Mimicking The Nano-Architecture Of Muscle For Impact Protection

Muscles play an important role in protecting our bodies. They act as a cushioning layer covering most of our brittle […]

Science Trends is a popular source of science news and education around the world. We cover everything from solar power cell technology to climate change to cancer research. We help hundreds of thousands of people every month learn about the world we live in and the latest scientific breakthroughs. Want to know more?