Figure 4

Strategies for therapeutic targeting of mutant TP53. 1: p53 turnover is dependent on E3 ligases such as MDM2 or CHIP that mediate ubiquitination and degradation of TP53. In tumor cells, TP53 protein as well as MDM2 and CHIP can be sequestered in high molecular weight complexes by chaperone proteins HSP70 and HSP90. This blocks the ubiquitin ligase activity of MDM2 and CHIP, leading to mutant TP53 accumulation which is fundamental for its GOF activities. Such accumulation can be targeted by drugs that disrupt TP53-chaperone binding, allowing proteosomal degradation of TP53. Furthermore, small molecules such as PK7088, APR-246 and NSC319726 have been shown to target specific or multiple forms of mutant TP53—Onco TP53—and promote TP53 refolding. This leads to restoration of TP53-dependent transcription and reactivation of TP53 biological responses such as cell-cycle arrest, senescence and apoptosis. It may also inhibit pathways associated with TP53 GOF, including binding and inactivation of TP53 family member proteins TP63 and TP73 ^{74, 100}