Developing corrector small molecules for reactivation of mutant p53 in cancer

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PROJECT SUMMARY The tumor suppressor protein p53 is the most frequently mutated protein in human cancers. About 600,000 new cancer patients in the United States are diagnosed each year with tumors expressing mutated p53. Most of the mutations associated with p53 are missense mutations that affect one of six hotspot sites in the DNA binding domain. These cancers express full length p53 that has lost tumor suppressor activity, but acquired gain-of-function oncomorphic properties that provide selective advantage to cancer cells. Therapeutic approaches targeting p53 are challenging and require reactivation of mutated p53. Developing such reactivation or corrector drugs is further complicated by very limited experience in pharma, biotech, and academia in this domain. These challenges in exploring novel therapeutic approaches by developing p53 corrector drugs have led to very slow, and limited success in clinical trials with proposed p53 reactivator compounds. However, one can argue that genuine p53 corrector drugs have not yet been tested in the clinic, because in vivo the available compounds (i.e. APR-246 and other thiol reactive molecules) are most likely not acting on mutant p53, but rather exploit redox-sensitivity of cells expressing p53 mutants. Development of genuine p53 mutant corrector drugs that bind p53 and restore a wild-type like conformation/activity in p53 cancer mutants, thus remains a crucial goal with potentially very high impact. We have developed a small molecule series that binds the L1/S3 pocket of mutant p53 and thereby restores DNA binding activity of mutant p53 in a reconstituted purified in vitro system. These results are reflected in induction of p53 target gene expression when cells harboring p53 hotspot mutants are exposed to these compounds. Furthermore, cell proliferation is halted and apoptosis is induced in a p53 mutant dependent manner. Importantly, growth of solid tumors carrying p53 mutants is blocked by this compound series in animal models. Tumors lacking p53 or expressing wild-type p53 are not affected by such treatment. These compounds provide strong support for feasibility to develop drug-like molecules that can restore tumor suppressor activity in p53 hotspot mutants. However, these compounds act in the low micromolar range in cell culture systems and activity needs to be improved to generate lead compounds for drug development. We propose two parallel approaches to achieve this goal. This proposal will generate promising lead compounds for mutant p53 corrector drug development.