p53 is a tumor suppressor protein that controls cell growth and tissue maintenance and plays a central role in preventing tumor suppression and development. It is a nuclear protein that functions as a transcription factor. p53 suppresses tumor development by triggering cell cycle arrest, apoptosis and/or senescence of incipient cancer cells.
When assembled into a tetramer, p53 shows sequence specific DNA-binding activity and activates expression of a number of genes involved in the DNA-repair mechanism, metabolism, cell cycle arrest, apoptosis and/or senescence. In cancer cells the p53 pathway is inactivated, which results in uncontrolled proliferation and genomic instability. In approximately 50% of cancers, p53 is inactivated by a missense mutation, a single base-pair substitution that result in translation of a different amino acid. 100+ different mutations have been identified in the p53 DNA-binding domain (DBD). p53 mutant proteins with mutations in the DNA-binding domain are broadly categorized into 2 main types – 1) DNA-contact mutants, 2) structural mutants, and 3) conformational mutants. The DNA-contact mutants preserve the wild-type conformation, but lose the ability to form strong contacts with DNA, thus losing transcriptional activity either completely or partially. Structural mutants exhibit localized structural distortions of the amino acid residues, but mostly maintain native-like thermodynamic properties. Conformational mutants are thermodynamically unstable and prone to rapid unfolding and aggregation. Both structural and conformational mutations are known to destabilize the active conformation of this highly flexible protein and disrupt its normal function. Furthermore, mutant p53 proteins exert dominant–negative effects (DNE) over wild-type p53 and cooperate with oncogenes for cellular transformation resulting in oncogenic gain-of-function properties.
The p53 pathway is activated in response to a broad variety of stress signals, such as gamma and UV irradiation, DNA damage, oncogene signaling, lack of nutrients, oxidative damage and etc. The level of the p53 response is carefully attenuated by posttranslational modifications of the amino acid residues of the p53 protein – phosphorylation, acetylation, methylation, ubiquitination, sumoylation, neddylation and etc. These posttranslational modifications affect the p53 conformation, its stability and ability to form protein complexes with its various partners.
Actavalon is developing small molecules capable of stabilizing the active conformation of mutant p53 proteins, thereby restoring tumor suppression activity and preventing oncogenic gain-of-function activities. This approach is applicable to many types of cancers irrespective of their tissue origin and driver mutations.