CP-31398

The inhibitory effect of RITA on human OSCC cell proliferation is mediated by apoptosis induction through p53 and Bax.

First, compounds targeting degradation or direct inhibition of WT p53, such as PM2, RITA, nutlin-3 and CH1iB, achieve p53 reactivation by affecting p53 inhibitors such as MDM2 and MDMX/4 or by preventing the breakdown of p53 by inhibiting the proteasomal complex. Second, compounds that directly affect mutated p53 by binding it and restoring the WT conformation and transcriptional activity (PRIMA-1, APR-246, COTI-2, CP-31398). Third, treatments that specifically affect HPV cancer cells by targeting the viral enzymes E6/E7 which are responsible for the breakdown of p53 such as Ad-E6/E7-As and bortezomib. In this review, we describe and discuss p53 regulation and its targeting in combination with existing therapies for HNSCC through a new classification of such cancers based on p53 mutation status and HPV infection.

Based on their structural similarity, these compounds resemble tyrosine kinase inhibitors and the p53 reactivator CP-31398...Moreover, the classical caspase-dependent pathway in leukemia was observed at a lower concentration, which again confirmed a multitargeted mechanism. It can therefore be concluded that the sulfonates of quinazolines can be regarded as promising scaffolds for developing anticancer agents.

Finally, the in vivo experimental evidence confirmed that CP-31398 with depleted Slug suppressed tumor growth by downregulating the Slug. Collectively, CP-31398-regulated Slug downregulation represses the p53-mutated EC via the p53/Wnt/Puma pathway.

In contrasts, nutlin-3a, an MDM2 inhibitor, increased p53 and p21 levels in mesothelioma with the wild-type p53 genotype and produced growth suppressive effects. Combination of CP-31398 and defactinib, a FAK inhibitor, also achieved synergistic inhibitory effects and increased p53 with FAK dephosphorylation levels greater than the single treatment. These data indicated that a p53-activating CP-31398 achieved growth inhibitory effects in combination with a MDM2 or a FAK inhibitor and suggested a possible reciprocal pathway between p53 elevation and FAK inactivation.