​P53 mutant gastric cancer organoid model

​P53 mutant gastric cancer organoid model.   PC14586 is a potential “first-in-class” small molecule p53 activator, used to stabilize the p53Y220C mutant, in which tyrosine is replaced by cysteine ​​at amino acid 220 of the protein.

PC14586 was granted Fast Track status by the US FDA in October 2020. Recently, PMVPharma announced that its activator PC14586, which precisely targets the p53Y220C mutant, has launched a phase 1/2 clinical trial aimed at treating patients with advanced solid tumors with p53Y220C mutations.

p53 is a well-known tumor suppressor gene, but in about 50% of human cancers, the DNA binding domain of p53 is inactivated by mutations. Mutated p53 has carcinogenic properties, giving cancer cells growth advantages and resistance to anti-tumor treatments. Among them, the p53Y220C mutation is the ninth common p53 mutation, accounting for 1.8% of all p53 mutations. The p53Y220C mutation has been observed in at least 30 different tumor types, including breast cancer, non-small cell lung cancer, colorectal cancer, pancreatic cancer, and ovarian cancer.

Mutant p53 has cancer risk (picture source: PMVPharma)

In addition to using drugs to restore the wild-type activity of the mutant protein in p53 therapy, another strategy is to inhibit the activity of the p53 mutant protein. When the activity of the p53 mutant protein cannot be directly inhibited, there are still ways to indirectly target the mechanism of the p53 mutant protein to promote tumor cell invasion, metastasis and survival. According to reports, there are multiple ways to target the p53 signaling network in cancer by restoring wild-type function, inhibiting mutant protein function, or targeting an out-of-control immune system.

Datasource: KEGG, BioCarta

PC14586 is a potential “first-in-class” small molecule p53 activator, used to stabilize the p53Y220C mutant, in which tyrosine is replaced by cysteine ​​at amino acid 220 of the protein. This single amino acid change creates a small gap in the p53 protein, making it unstable and unable to effectively interact with DNA. Currently, PC14586 is being developed for the treatment of patients with advanced solid tumors whose p53Y220C mutations have been confirmed by next-generation sequencing.

In order to facilitate the development of targeted drugs for p53 mutations, Keyu Medical has successfully constructed an in vitro tumor class with drug safety, tolerability, pharmacokinetics and anti-tumor activity for patients with p53 mutation tumors through tumor organoid R&D technology. Organ research models, involving mutations such as Y163C, Q104+, R273H, Y234C, R342P, R196, Y220C, V203E (see Table 1 for related products), including organoid models of gastric cancer with p53Y220C mutation (CAT#: KO- 41277) The relevant information is as follows:

Bright field photo of KO-41277 product

KO-41277 product HE dyeing result chart

Sanger sequencing results of KO-41277 product (up: forward sequencing; down: reverse sequencing)

Table 1 Product information table related to p53 mutation

Note: The types of driver mutation genes contained in the above products are not fully listed. For details, please contact us.

(source:internet, reference only)

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