P53 tumor suppressor gene mutations occur in the majority of human cancers and 
contribute to tumor development, progression and therapy resistance. Direct 
functional restoration of p53 as a transcription factor has been difficult to 
achieve in the clinic. We performed a functional screen using a 
bioluminescence-based transcriptional read-out to identify small molecules that 
restore the p53 pathway in mutant p53-bearing cancer cells. We identified CB002, 
as a candidate that restores p53 function in mutant p53-expressing colorectal 
cancer cells and without toxicity to normal human fibroblasts. Cells exposed to 
CB002 show increased expression of endogenous p53 target genes NOXA, DR5, and 
p21 and cell death which occurs by 16 hours, as measured by cleaved caspases or 
PARP. Stable knockdown of NOXA completely abrogates PARP cleavage and reduces 
sub-G1 content, implicating NOXA as the key mediator of cell death induction by 
CB002. Moreover, CB002 decreases the stability of mutant p53 in RXF393 cancer 
cells and an exogenously expressed R175H p53 mutant in HCT116 p53-null cells. 
R175H p53 expression was rescued by addition of proteasome inhibitor MG132 to 
CB002, suggesting a role for ubiquitin-mediated degradation of the mutant 
protein. In summary, CB002, a p53 pathway-restoring compound that targets mutant 
p53 for degradation and induces tumor cell death through NOXA, may be further 
developed as a cancer therapeutic.