Current trends in clinical trials and the development of small molecule epigenetic inhibitors as cancer therapeutics

Abstract

Epigenetic mechanisms control and regulate normal chromatin structure and gene expression patterns, with epigenetic dysregulation observed in many different cancer types. Importantly, epigenetic modifications are reversible, offering the potential to silence oncogenes and reactivate tumor suppressors. Small molecule drugs manipulating these epigenetic mechanisms are at the leading edge of new therapeutic options for cancer treatment. The clinical use of histone deacetyltransferases inhibitors (HDACi) demonstrates the effectiveness of targeting epigenetic mechanisms for cancer treatment. Notably, the development of new classes of inhibitors, including lysine acetyltransferase inhibitors (KATi), are the future of epigenetic-based therapeutics. We outline the progress of current classes of small molecule epigenetic drugs for use against cancer (preclinical and clinical) and highlight the potential market growth in epigenetic-based therapeutics.

Plain language summary

Cancer affects a lot of people worldwide – about one in every two individuals will face it in their lifetime. Although cancer rates are going up, survival rates have also improved in many cases, largely thanks to better and more specific drugs. These new drugs target specific changes in tumors, which are identified using molecular testing. These changes can be in the deoxyribonucleic acid (DNA) sequence, or in the ‘epigenetics’, which does not change the DNA sequence. Importantly epigenetic changes can be reversed, unlike DNA changes. This opens up the possibility of targeting these epigenetic changes to treat cancer, potentially turning back on anti-cancer processes that were turned off. Scientists are now working on developing new drugs that target these epigenetic changes. These drugs, called small molecule epigenetic inhibitors, have shown promise in improving the effectiveness of cancer treatment. They're opening up new options for treating various diseases, including cancer. Lots of new epigenetic drugs are being developed and tested, with some already moving into clinical trials with a few already in use to treat cancer patients. In this summary, we'll discuss the progress of these drugs, how they are being used against cancer, and the growing interest in epigenetic-based therapies.

Tweetable abstract

We review development of small molecule epigenetic anti-cancer therapeutics and outline the progress of epigenetic drug development, preclinical and clinical trials, highlighting market growth in epigenetic-based therapeutics.

Graphical abstract

Executive summary

The challenge

• Worldwide the incidence of cancer is now almost 1 in 2.

• Increasing rates of cancer requires new targeted therapeutic options to improve patient survival.

• The common dysregulation of epigenetics observed in many tumors offers a promising new opportunity for the development of new specific and targeted treatments.

• New classes of drugs offer new development and investment opportunities for pharma.

Small molecule epigenetic inhibitors

• Epigenetic inhibitors are an exciting new class of therapeutics.

• New classes of epigenetic drugs are undergoing clinical trials, with the recent approval of one drug for the treatment of a solid tumor type (breast cancer).

• The epigenetic market is growing substantially.

Conclusion

• The development of new epigenetic inhibitors will lead to new clinical approvals for cancer treatment.

• The expanding clinical use of small molecule epigenetic inhibitors will lead to a significant expansion of the market, with increasing returns for patients, and pharma.

Keywords: :

• acetyltransferase
• cancer
• epigenetic
• HAT
• inhibitor
• KAT
• lysine
• precision
• small molecule
• targeted
• therapeutic

Author contributions

JAL Brown: manuscript writing, final approval of manuscript. N Zohourian: manuscript draft and writing, data collection.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Acknowledgments

The authors apologize that not all relevant papers could be cited due to space limitations.