The Guardian of the Genome: p53
- Nick Inboden
- Aug 22, 2024
- 5 min read
The TP53 gene is a tumor suppressor gene responsible for producing the p53 protein found throughout the human body. The p53 protein is responsible for a wide variety of tasks in regard to tumor and cancer suppression as it is able to repair damaged DNA, stop the process of cell division, and even induce cell death. When the TP53 gene is mutated or inactive, the processes detailed above do not occur as a wrong form of p53 protein is produced leading to cancer and tumor growth. Given the importance of the TP53 gene, it makes sense that, according to Nature, it is the most researched gene in human history. This wide research regarding the gene has led TP53 to be called the “guardian of the genome.” This article delves into past therapeutics aimed at targeting the TP53 gene and p53 protein and why despite numerous attempts at restoring normal functionality of p53, no p53 therapeutics exist in either the US or European markets.
Approaches to Treatments
Genes contain the necessary information for the production of proteins. If this information is damaged or altered, the protein that is produced will also be damaged or altered. Given that the TP53 gene is responsible for coding the tumor suppressor protein p53, mutations in the TP53 gene result in changes to the p53 protein leading to deactivation of the protein responsible for regulating cell growth.
One can think of the deactivated or damaged protein like a football without air in it. The structure of the football is different and therefore the football is harder to throw, less accurate, doesn’t travel as far as you would like it to, and doesn’t work well to achieve its purpose. A small molecule, like a drug, can be thought of as air that is put into the deflated football which causes a change in the structure and restores normal function. The same way in that the air causes a change in the physical structure and shape of the football, small molecules can do the same to targeted proteins.
While attempting to target a specific protein to stabilize or change the shape in order to restore normal function, one must have an idea of what the mutated form of protein looks like. This is made even more difficult in that there exist multiple mutations resulting in differently shaped proteins. With recent advancements in computational biology, like that of AlphaFold (read here), researchers are coming up with more and more effective ways to not only discover, but also test potential drug candidates for various mutations.
In 1999, CP31398, a compound identified by Pfizer, was noted to have restored the activity of p53 and reduced tumor growth in preclinical trials. The normal state of p53 was stabilized by the drug and therefore normal protein function was restored. Unfortunately, after more research into CP31398 was performed, non-specific toxicity occurred which prevented CP31398 from continuing into clinical trials.
APR-246 was another compound used to target p53. APR-246 is a derivative form of PRIMA-1, a compound discovered in 2002 that restored normal p53 function and resulted in apoptosis.
Apoptosis is a programmed cell death that is used to eliminate undamaged or unwanted cells. Apoptosis occurs naturally in the body and is important in the prevention of diseases like cancer that originate from cells containing dangerous mutations.
Although PRIMA-1 never entered into clinical trials due to unmanageable toxicity, APR-246 did. APR-246, now known as Eprenetapopt, is still currently in clinical trials being used in combination therapy with Azacitidine for individuals with mutated TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The combination therapy has shown potentially promising results and further evaluation of the therapy is expected.
Evolving Preclinical Trial Standards
One issue in regard to developing p53 therapeutics is that in vivo preclinical testing occurs primarily in mice. While mice are commonly used and are regarded as generally good models for testing toxicity and efficacy, differences in genetic sequences of p53 and p53 signaling pathways contribute to difficulty in gauging whether or not a p53 therapeutic will perform well in clinical trials. Unmanageable toxicity is the reason that 30% of drugs entering clinical trials fail and previous developments, like that of CP31398, despite not entering clinical trials, are indicative of the difficult nature of developing a non-toxic therapeutic targeting p53.
As alluded to in this article and previous articles, new technology that can predict properties of drug candidates and perform preclinical toxicology screening is being developed and utilized more and more. One of the most commonly used tools is SwissADME.
SwissADME was developed by researchers at the University of Lausanne Molecular Modelling Group and the SIB Swiss Institute of Bioinformatics. SwissADME, in addition to SwissDock, and SwissTargetPrediction, is a tool to help predict properties of a drug to provide researchers with information about how a drug is likely to interact with the body. One of the more intriguing aspects of the tool is the BOILED-Egg model (Brain Or IntestinaL EstimateD permeation). Depicted below for Adderall, a drug that is often used in the treatment of ADHD, the BOILED-Egg model provides a visual of how effective a drug will be at penetrating the Intestinal layer and Blood-Brain barrier (BBB). With the white of the diagram representing the Intestinal layer and the yellow representing the BBB, the diagram resembles a boiled egg. Since Adderall works via the brain, it is imperative that the drug can cross the Blood-Brain barrier. Using SwissADME and the BOILED-Egg model, we can see that Adderall achieves permeance of the BBB below:
Although originally developed in the late 1920s, current researchers could use tools like SwissADME to predict effects of variations of drugs like Adderall. If this same paradigm is applied to the drugs targeting p53 that failed in preclinical trials, more efficient drug design would occur enabling researchers and pharmaceutical companies alike to produce drugs that are more likely to succeed in stabilizing p53 and preventing cancer formation. Coupled with other tools like SwissTargetPrediction and SwissDock, the amount of time and resources spent in preclinical testing would significantly decrease leading to more impactful healthcare products for the general public - a big advancement in biotechnology.
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SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. (2017) 7:42717.
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