What are the important developments of innovative therapies developed around p53 targets in the past 40 years?

Article source: Pharmaceutical Guanlan

There is an amazing gene hidden in each of us-TP53, its existence ensures the normal growth and division of cells, thereby protecting the human body from cancer

However, recently, more and more innovative therapies developed around p53 have received good news

▲Common TP53 mutations in 16 cancer types (picture source: reference [1])

Genome Guardian

Among the many genes related to cancer, TP53 is undoubtedly one of the most thoroughly studied by humans

How does p53 play a specific role in suppressing cancer? According to the book "p53: the gene that cracks the cancer code", p53 constantly checks human cells every day to ensure that they do not make mistakes during the process of growth and division

If the error cannot be repaired and the cells are at risk of becoming cancerous, p53 will limit the harmful consequences of gene mutations

In normal cells, p53 is maintained at a low level by a series of regulatory factors

With the protection of p53, why does the human body still have cancer? Studies have shown that when p53 itself is damaged or other abnormalities in the system cause p53's "cancer suppression" function to weaken, cancer may take the opportunity to invade

▲Different mechanisms can lead to different phenotypes of p53 mutations: (A) wild type, (B) loss or partial loss of function, (C) function selection, (D) new form/function gain (picture source: reference [1] )

Therefore, for a long time, p53 has been considered the key to cancer treatment

Break through the barrier, start from restoring protein function

Although the research on p53 is very detailed, innovative therapies around this target have not been born for more than 40 years

In contrast to the drug development approach that targets oncoproteins, the development of p53 targeted drugs needs to restore (rather than inhibit) the normal activity of the protein in order to inhibit the occurrence and development of tumors

▲Tumors targeting p53 mutations (picture source: reference [1])

After years of research and development, researchers have developed small molecules and peptides that can stabilize the structure of unstructured mutant proteins.

The p53 activator PC14586 from PMV Pharma has also launched a phase 1/2 clinical trial and is being developed for the treatment of patients with advanced solid tumors whose p53 Y220C mutation has been confirmed by next-generation sequencing

Another drug candidate entering the clinical trial stage is the familiar arsenic trioxide

Different routes lead to the same goal, more innovative therapies are being developed

In addition to directly restoring the function of the p53 protein, many researchers have also started from other aspects of the p53 signaling pathway

▲The role of MDM2 inhibitors (picture source: reference [1])

Take KRT-232, a product under development by Kartos Therapeutics as an example.

Another small molecule MDM2 inhibitor, APG-115, developed by Ascent Pharmaceuticals, has obtained positive results in phase 2 clinical trials for patients with unresectable/metastatic melanoma or advanced solid tumors, and will be presented at the 2021 ASCO annual meeting Show in the form of an oral report

Synthetic lethality is also one of the attractive strategies for targeting tumors with p53 mutant proteins
.
"Cell" magazine once pointed out that the weaknesses caused by many p53 mutant proteins are related to DNA damage response (DDR) and metabolism
.
Although p53-deficient cells can avoid apoptosis in the face of DNA-damaging drugs, further damage to the DDR system will make tumors with p53 mutations very sensitive to genotoxic damage
.
Using this "synthetic lethal" concept, people are developing strategies to combine drugs that cause DNA damage with inhibitors such as ATM, CHK2, ATR, and CHK1 in the DDR system
.

Among them, MDM2+Bcl-2 is a combination that has attracted much attention
.
It is reported that the combination therapy can stimulate a "synthetic lethal" mechanism in a variety of cancers, that is, simultaneously block the two key pathways of MDM2-TP53 and Bcl-2, which are used by tumor cells to escape apoptosis, resulting in no way for tumor cells to escape.
, And then die
.
At present, the combination of APG-115 (MDM2 inhibitor) and APG-2575 (Bcl-2 inhibitor) from Ascent Pharmaceuticals, as well as idasanutlin (MDM2 inhibitor) and venetoclax (Bcl-2) from Roche and AbbVie (AbbVie) Inhibitors) have entered the clinical stage
.

Another target called Wee1 has gradually entered people's field of vision.
It is an important kinase related to the DDR pathway
.
Studies have shown that Wee1 has a certain synthetic lethal effect with TP53 mutations that are widely present in tumor cells
.
It is reported that some Wee1 inhibitors have shown certain clinical efficacy in multiple tumors, especially tumors with TP53 mutations
.
Among them, AstraZeneca (AstraZeneca) targeted DNA damage repair mechanism of research therapy AZD1775, is in dozens of clinical studies to test its single agent or combination of drugs for the treatment of ovarian cancer and various solid tumors
.
In China, the Wee1 inhibitors under development of Impair Pharmaceuticals and First Pharmaceutical Holdings have been approved for clinical trials this year
.

In addition, researchers are also developing potential therapies based on innovative technologies such as PROTAC (targeted protein degradation chimera) and mRNA, as well as combination therapies with a variety of different mechanisms of action, to explore their potential in the treatment of cancers with p53 mutations
.

Although no therapies have been successfully approved yet, given that p53 mutations are so common in human cancers, the development of new drugs in this field can be described as a blue ocean, and p53 targeted drugs are widely called the holy grail of the targeted field by the scientific and industrial circles.

.
We look forward to this day soon
.

Reference materials:

[1]Kastenhuber, Edward R, Lowe, et al.
Putting p53 in Context.
[J].
Cell, 2017.

[2] Prasad, V.
Perspective: The precision-oncology illusion.
Nature 537, S63, doi:10.
1038/537S63a (2016).

[3] Chen S, Wu JL, Liang Y, et al.
Arsenic Trioxide Rescues Structural p53 Mutations through a Cryptic Allosteric Site-ScienceDirect[J].
2020.

[4] Suyong Choi et al.
, (2019), A nuclear phosphoinositide kinase complex regulates p53, Nature Cell Biology, DOI: https://doi.
org/10.
1038/s41556-019-0297-2

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