Transcription and Translation Inhibitors in Cancer Treatment

Abstract

Transcription and translation are fundamental cellular processes that govern the protein production of cells. These processes are generally up regulated in cancer cells, to maintain the enhanced metabolism and proliferative state of these cells. As such cancerous cells can be susceptible to transcription and translation inhibitors. There are numerous druggable proteins involved in transcription and translation which make lucrative targets for cancer drug development. In addition to proteins, recent years have shown that the "undruggable" transcription factors and RNA molecules can also be targeted to hamper the transcription or translation in cancer. In this review, we summarize the properties and function of the transcription and translation inhibitors that have been tested and developed, focusing on the advances of the last 5 years. To complement this, we also discuss some of the recent advances in targeting oncogenes tightly controlling transcription including transcription factors and KRAS. In addition to natural and synthetic compounds, we review DNA and RNA based approaches to develop cancer drugs. Finally, we conclude with the outlook to the future of the development of transcription and translation inhibitors.

Keywords: cancer; drug; inhibitor; transcription; translation.

Figure 1

A simplified overview of the four stages of transcription and where the inhibitors are targeting. Pol II, RNA polymerase II; TFIID, transcription factor IID; CDK, cyclin dependent kinase.

Figure 2

Chemical structures of RNA polymerase inhibitors.

Figure 3

Chemical structures of various bromodomain inhibitors (JQ-1, birabresib, and miverisib) and triptolide.

Figure 4

Chemical structure of the nucleoside analogs that function as premature transcription chain terminators.

Figure 5

Chemical structures of selected CDK inhibitors.

Figure 6

A simplified overview of the four stages of translation and where the inhibitors are targeting.

Figure 7

Selected chemical structures of inhibitors that target the mTOR complexes. Top contains the rapamycin, and its water-soluble analogs, rapalogs. In the middle there are some of the second generation of mTORC inhibitors which target the kinase activity. On the bottom, one of the third generation mTOR inhibitors is shown, which connects rapamycin scaffold with a second-generation kinase inhibitor.

Figure 8

The chemical structures of silvestrol and omacetaxine.

Figure 9

Molecules that target transcription factors and are in clinical trials or close to starting them. RG-7388 and HDM-201 are PPI inhibitors, SY-1365 is a selective CDK7-inhibitor and INCB057643 and BMS-986158 are BET inhibitors that block the transcription of many transcription factors, including c-Myc.