Background: In clinical oncology, there are about 80 approved small-molecule targeted drugs. Most of them target oncoproteins whereas none targets tumor suppressor (the below figure). Mechanistically, a oncoprotein-targeting drug just need to inhibit protein function, with the molecular mechanisms of how a small molecule binds and inhibits protein is clear and understandable. However, a tumor suppressor-targeting drug need to restore function to protein, with the molecular mechanism of how a small molecule binds and restores function to a protein remains elusive and unconceivable. Indeed, there is no successful precedent of a drugged tumor suppressor.

Aim: We are working within a research direction opposite to the current targeted therapy — restore rather than inhibit protein function, aiming to drug the undruggable tumor suppressor such as p53 and PTEN with rationally designed targeted strategy.

Works: There are over 1000 diverse p53 mutants and the field has been seeking for a one-size-fits-all compound that is able to restore function to all of the p53 mutants for decades. We think there may be no such compound, and accordingly classified the hundreds of p53 mutants into several types based on their diverse inactivation mechanisms; we focused on the structure p53 mutants (a type of p53 mutants that are hardly folded in cells) and proposed a strategy by using small molecule to mimic disulfide bond to glue p53 intramolecular domains; in 2020 we obtained Arsenic Trioxide (ATO) that could rescue p53 mutants with potencies higher than the reported rescue compounds by several orders of magnitude (ATO has been rapidly and widely validated as an effective mutant p53 rescue compound by academic and industry since we published the data in Cancer Cell and STAR Protocols); revealed the atom-level mechanism of how arsenic atom acted as a intramolecular glue by gluing LSH domain and β-sandwich domain of p53, and thus stabilizing p53 structure (this makes the mechanism how to restore function to a protein not “elusive and unconceivable” any more). We are translating the arsenic-rescue-p53 findings into clinics, designing dual-specificity small molecule (one target is mutant p53), pharmacologically targeting PTEN, treating LFS mouse with p53 germline mutation, eliminating the cancer risks caused by the enrichment of p53 mutation during application of iPSC and CRISPR techniques, and etc.

Figure legend: Among the 100 most frequently mutated genes in cancer, 51 are tumor suppressors and 26 are oncogenes. Although tumor suppressor proteins are the most widely mutated proteins in cancer, none of them are drugged.

Figure legend: The potencies of ATO in rescuing thermal stability, protein folding and transcriptional activity of p53 structural mutants are at least 100-1000 times higher than the dozens of p53 rescue compounds reported by 2020 (comparison outcomes of ATO and the eight widely reported p53 rescue compounds are shown. The treatment dosages are titrated for each compound and the optimized dosage was then used for each compound in the comparison).