p-nitro-Cyclic Pifithrin-α is an inactivator of p53.

The activation of the tumor suppressor gene p53 plays a key role in regulating the in-vitro death of neurons, following apoptotic stimuli molecules including glutamate and DNA-damaging agents. Thus, p53 inhibitors may prove effective in suppressing the degenerative processes in neurodegenerative disorders.

In vitro: Pifithrin-α (PFT-α) was identified as an inactivator of p53 blocking p53-dependent transcriptional activation and apoptosis. Cyclic PFT-α was a stable analog of PFT-α. p-nitro-Cyclic PFT-α, a cell-permeable form of cyclic PFT-α, was found to be one order of magnitude more active than PFT-α in protecting cortical neurons exposed to etoposide. p-nitro-Cyclic PFT-α acted in a p53-dependently but did not block phosphorylation of p53 on Ser15 in response to etoposide treatment, although it prevented p53 posttranscriptional activity [1].

In vivo: In a previou study, C57BL/6 mice were fed a high-fat (HFD) or control diet for 8 weeks; PFT was administered three times per week. Results showed that PFT administration could suppress HFD-induced weight gain, steatosis, oxidative stress, ALT elevation, and apoptosis. PFT treatment also able to blunt the HFD-induced upregulation of miRNA34a and increase SIRT1 expression. In the livers of HFD-fed, PFT-treated mice, activation of the SIRT1/PGC1α/PPARα axis increased the expression of malonyl-CoA decarboxylase [2].

Clinical trial: So far, no clinical study has been conducted.

References:
[1] .  Pietrancosta, N.,Moumen, A.,Dono, R., et al. Imino-tetrahydro-benzothiazole derivatives as p53 inhibitors: Discovery of a highly potent in vivo inhibitor and its action mechanism. Journal of Medicinal Chemistry 49(12), 3645-3652 (2006).
[2] Derdak Z, Villegas KA, Harb R, Wu AM, Sousa A, Wands JR.  Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease. J Hepatol. 2013 Apr;58(4):785-91.