The p53 tumor suppressor is inactivated in most cancers, thus suggesting that loss of p53 is a prerequisite for tumor growth. Therefore, its reintroduction through different means bears great clinical potential. Kenner and colleagues review small molecules, which are currently developed and able to reactivate specific, frequently observed mutant forms of p53 or that inhibit the negative regulator MDM2. However, despite the beauty of the concept and advances in medicinal chemistry, the past years have shown that many obstacles have to be overcome to bring p53 reactivation to the clinic on a broad scale, and it is likely that in most cases it will be part of a combined therapeutic approach. However, improving current p53 targeted molecules and finding the best therapy partners might improve cancer therapy in the not so distant future.
p53 mutations that disrupt DNA binding or destabilize protein folding and substances that can rescue these mutations. Mutations at sites 248 and 273 are the most frequently detected in cancer and are involved in direct binding to DNA. Small molecules that restore DNA binding (collectively denoted by X in the diagram) are not mutation site-specific and include PRIMA, APR-246, CP31398, Ellipticine analogs and JNJ26854165.