All the p53 drugs are still early stage, and will be interesting to see which ones prove useful. It may be that some drugs will only work with specific p53 mutations, and perhaps combo chemo / radiation / immunotherapy will be the way to go. It's still VERY early in the game, and I like our chances.
From the COTI-2 paper:
"However, there were other cell lines such as HCT-115, H292, and H460 with wild type P53 that were also highly sensitive to COTI-2 treatment. This suggests that COTI-2 may affect mutant P53 in human tumors, but likely has additional effects on other targets in the PI3K/AKT/mTOR pathway."
Don't know if they looked at the effects of activation on wild-type p53, but it apparently does more than just re-activate mutant p53.
Re: PRIMA-1 byproducts and metabolites, I believe they are using methylated PRIMA-1, which may have different byproducts. Haven't heard about AEs in APR-246. There are always good possibilities that new drugs have some toxicity.
APR-246 AML paper also shows it works in p53 mutant and p53 wild-type cells:
"Also, the fact that APR-246 is effective in both mutated and non-mutated AML cells might be explained p53-independent mechanisms of action."
Some more on APR-246 p53 mutant dependent and independent MOAs:
"Its main cellular mechanism of action is the induction of apoptosis, mediated by the caspase activation. PRIMA-1 as well as APR-246 triggers an upregulation of genes involved in cell cycle control and apoptosis in mutant-p53 and wild-type p53 cancer cells. Anyway, 15 years after their discovery, it clearly appears that PRIMA-1/APR-246 have also p53-independent effects, as oxidative and ER stress, which emphasize their efficacies and extend their possible clinical uses, on tumor cells, independently of the p53 status."
Molecular biology of cancer is very complicated. Hoping that these p53 drugs play out well, especially kevetrin.
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