Startegy for new drug: Restart the apoptosis process of cancer cells
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Startegy for new drug: Restart the apoptosis process of cancer cells
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Startegy for new drug: Restart the apoptosis process of cancer cells.
Restart the apoptosis process of cancer cells: Provide a new strategy for the design of anticancer drugs
Cancer cells are evolved from normal cells and have three characteristics: infinite proliferation, transformation and easy transfer. What it boils down to is that cancer cells mutate key genes and reprogram the expression of thousands of related genes to promote rapid cell growth and block pathways that induce cell death.
Over the past decades, mutated genes that drive malignant cell proliferation, survival, invasion, and metastasis have been identified in a variety of cancers. In addition, independent research has identified the programmed death pathway by which harmful cells are eliminated for the benefit of the body.
Unfortunately, these death pathways appear to be disabled in cancer cells for a variety of reasons. So, if you somehow reactivate the cancer cell’s death pathway, you can wipe out the tumor completely.
On July 26, 2023, researchers from Stanford University published a research paper entitled: Rewiring cancer drivers to activate apoptosis in Nature .
The study turned a protein that promotes cancer by repressing the transcription of various genes — BCL6 — into part of a transcriptional activator, resulting in a new class of compounds that kill cancer cells.
This discovery will provide a new strategy for designing new anticancer drugs and open up new avenues for cancer treatment.
BCL6 is a master regulator of germinal center B cells, which are produced in normal immune responses but are also the cell of origin for a type of cancer called diffuse large B-cell lymphoma (DLBCL) .
More specifically, BCL6 directly represses genes encoding cell cycle inhibitors involved in a form of programmed cell death known as apoptosis.
Furthermore, BCL6 prevents the irreversible differentiation of germinal center B cells into plasma cells by repressing the gene encoding the transcriptional repressor protein BLIMP-13, thereby maintaining the identity of germinal center B cells.
However, BCL6 is often dysregulated in DLBCL, resulting in a hyperproliferative state of this cancer cell.
In this study, Dr. Sai Gourisankar and colleagues decided to try to alter the transcriptional role of BCL6 through the concept of chemically induced proximity (CIP) .
CIP exploits a core principle of cell biology that cellular regulation often involves the induction of two different proteins in close proximity to each other.
A strategy to alter the action of transcription factors
In fact, induced proximity underlies many forms of biological regulation, including receptor function, post-translational modification, transcriptional regulation, and epigenetic regulation, among others.
In recent years, this process has also been modified and developed for basic research and clinical treatment, such as PROTAC technology, which uses artificially designed dimer small molecules to bind target proteins and guide them to the proteasome for degradation.
From this point of view, it is also feasible to use CIP to reactivate apoptosis to kill cancer cells.
In the latest study, published in Nature , the research team synthesized a small dimeric compound with a BCL-binding molecule at one end and a BRD4-binding molecule, a protein that activates transcription, at the other end.
This first-of-its-kind compound binds BRD4 and BCL6 to form a complex, thereby using BRD4 to activate the expression of genes normally silenced by BCL6.
The research team named this brand new compound transcriptional/epigenetic chemical proximity inducer 1 (TCIP1) .
The production model of TCIP1
As expected, TCIP1-treated diffuse large B-cell lymphoma (DLBCL) cell lines upregulated the expression of hundreds of genes, many of which are known targets of BCL6. Even more exciting, TCIP1 effectively killed BCL6-expressing DLBCL cells in vitro, suggesting that TCIP1 could serve as a potential new anticancer drug.
It is worth mentioning that many compounds have been identified that can inhibit or degrade BCL6, thereby alleviating the repression of its target genes and killing DLBCL cells in vitro.
However, because these compounds work through a “loss-of-function” mechanism, they likely require almost complete inhibition of BCL6 to be effective. In contrast, TCIP1 uses a “gain-of-function” mechanism, meaning that only a small fraction of cellular BCL6 is required to function.
This may be useful in the treatment of bulky but poorly vascularized tumors where high drug concentrations are difficult to obtain.
TCIP1 rapidly activates BCL6 target genes by recruiting BRD4
The research team also observed that, in addition to upregulating the expression of many tumor suppressor genes, TCIP1 also downregulated MYC, a tumor-promoting gene encoding a transcription factor, and many of its transcriptional targets—a possible explanation for the drug’s abnormal toxicity to lymphoma cells. s reason.
The mechanism by which TCIP1 downregulates MYC is unclear, but one possibility is that the compound upregulates the BCL6 target BLIMP-1, which subsequently inhibits MYC; alternatively, TCIP1 may recruit BCL6 to some BRD4-targeted genes, including MYC , thereby inhibiting their expression.
TCIP1 inhibits MYC and its targets while activating pro-apoptotic
Interestingly, the TCIP approach also has general applicability and is not limited to BCL6 as a tumor regulator.
In cancer, many transcription factors are frequently dysregulated, but unlike BCL6, most of these factors activate the transcriptional processes of associated genes.
Therefore, any TCIP designed to target these factors will require the recruitment of transcriptional repressors.
This diversity of development is also a spectacle—the development of TCIP is only limited by the imagination and creativity of cancer biologists, and its possibilities are endless.
Toxicity of TCIP1 in mouse and primary human cells
Taken together, this new study highlights the potential of the dimeric small-molecule compound TCIP1 as a therapeutic potential for diffuse large B-cell lymphoma (DLBCL) and a wider range of cancer types, and may become a new type of anticancer drug in the future.
However, given the complex mechanism of TCIP1, careful experimental review is still needed to discern how this novel compound alters gene expression and biological outcomes, and how safe this drug is in humans, whether there are serious adverse effects. Toxic and side effects, these problems all need to be solved urgently.
Paper link :
https://www.nature.com/articles/s41586-023-06348-2
https://www.nature.com/articles/d41586-023-02213-4
Startegy for new drug: Restart the apoptosis process of cancer cells
(source:internet, reference only)
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