In contrast to traditional cancer treatment techniques like chemotherapy and radiotherapy that were widely used in the past decades, now immunotherapy has entered people’s view due to its remarkable benefits. Immune checkpoint inhibitors share a contributory role in immunotherapy.
Normally certain proteins would be made by some types of immune system cells (like the famous T cells) and the main function of these proteins is to help keep immune responses in check and T cells from killing cancer cells. When the body is in health, they are doing the just right thing; however, they might help cancer cells escape. Given this, scientists begin to use immune checkpoint inhibitors to block these proteins, which let go of the brake and allows the immune system and T cells to perform their roles of killing cancer cells.

Currently, there are several promising pharmaceutical class of immune checkpoint inhibitors and some are still in the preclinical stage. In this article, we are going to talk about tree types, i.e. IDO inhibitors, HDAC inhibitors, JNK inhibitors. All might usher the next fundamental breakthrough in the field of immunotherapy.

IDO inhibitors

IDO (full name: indoleamine 2, 3-dioxygenase) is an enzyme that breaks down the amino acid tryptophan. It was found to become activated during tumor development in some experiments, and in a sense helping malignant cells escape detection of our immune system. Therefore, IDO inhibitors are very important in helping to promote an enhanced immune response against the tumor by blocking the IDO enzyme which reduces the depletion of tryptophan. In addition, they can also offset the immunosuppressive effects of tryptophan metabolites.

One fact about IDO inhibitors is that they have only limited anti-tumor efficacy on their own; however, once combined with other drugs (for example, anti-PD-1 in most cases), they demonstrate great potentials and can achieve very ideal outcome. Another merit is their significantly lower treatment-related toxicities compared with other drugs with similar effects. In general, the future for IDO inhibitors and their combinations is bright. Recently, with the advance of in silico drug design and library screening, some potent IDO inhibitors have been identified. So far, three IDO inhibitors - Epacadostat, Indoximod and Navoximod- have successfully progressed into clinical trials, yet none of them has gained approval from regulatory agencies.

HDAC inhibitors

As limitations of traditional treatment methods began to be surfaced, researchers decided to think differently as they found gene expression played a vital role in cancer progression and resistance.
With this factor being considered, agents that can modify the epigenetic environment of tumor might be utilized in cancer treatment. As a family of eleven zinc-dependent enzymes, HDAC (histone deacetylase) inhibitors are representatives of these anticancer agents. After their therapeutic implications were clarified, many more HDAC inhibitors become study of focus in the research circle. Two of their representatives — vorinostat and depsipeptide — have recently gained FDA approval for treating T-cell lymphoma.

HDAC inhibitors are not only promising therapeutic targets in cancer research, but also widely used in a wide range of diseases, such as neurological diseases, immune disorders, parasitic and inflammatory diseases.

JNK inhibitors

Just like HDAC inhibitors mentioned above, JNK inhibitors also enjoy a spanning range of therapeutic applications as this family of protein kinases plays a central role in areas of regeneration, cell death, gene expression, neuronal plasticity, and regulation of cellular senescence.

JNKs have basically become a focus of screening strategies aiming for new therapeutic approaches to common diseases like diabetes or cancer. Second, JNK inhibitors are closely related with pathological cell death resulting from neurodegenerative diseases like Alzheimer’s disease (AD). This is because activation of JNK was found to have a stake in regulating apoptosis signals. Besides, findings from in vitro and in vivo studies have reported likely association between alterations of JNK pathways with pathogenesis and neuronal death in AD. Therefore, it is reasonable enough to say that JNK inhibitors are potential target for treating neurodegenerative mechanisms associated with AD. In addition, JNK inhibitors are also promising agents in multiple inflammatory diseases. With more efforts being put in, some yet unknown advantages over steroid therapy may also be unveiled.

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