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Restoring the guardian: p53 tumor suppression without toxicity​

  • Therapeutics
  • 2023

p53 remains the best-studied and most common tumor suppressor gene, but the gene is mutated in half of all tumors rendering its activity useless  in stopping cancer growth. For decades, researchers have sought to increase p53 activity. Results in the field have thus far been disappointing, largely due to toxicity mediated by efforts to restore p53 activity via small molecule approaches.  However, the team of Prof. Dipanjan Chowdhury, PhD, chief, Division of Radiation and Genome Stability and Svanberg Family Chair, David Scott, PhD, director, Medicinal Chemistry Core, and Sirano Dhe-Paganon, PhD, director, Structural and Chemical Biology Center at Dana-Farber have a new approach supported by the Accelerator — developing small molecule inhibitors of Tudor-interacting repair regulator protein (TIRR) to be used in patients with tumors that retain at least one copy of wild-type p53.   

The most well-studied approach for restoring p53 has been by inhibiting the MDM2 protein. However, clinical trials of at least ten MDM2 inhibitors show that while they increase p53 levels, that increase has been too toxic for the body. Therefore, the identification of targets that activate p53 without boosting their levels remains a competitive area of drug discovery and one with potentially significant promise in treating many cancers.  

Several years ago, Dr. Chowdhury and his team discovered TIRR, a novel p53-associated protein, but they were not aware of its mechanism of action on p53 at the time. Since then, the team discovered that TIRR inhibition activates the tumor suppressor functions of normal, wild-type p53 leading to cancer cell death. Since half of all cancers retain at least one copy of wild-type p53 this therapeutic strategy may be widely applicable to multiple tumor types, and a potential approach that avoids the toxicity seen with previously developed MDM2 inhibitors.   

Activating p53 has been the holy grail of cancer drug discovery.

Dipanjan Chowdhury, PhD

The researchers found that TIRR affects selective functions of the gene such that it is not harmful to normal cells. Studies in TIRR-knockout mice revealed increased p53 activity but the animals showed no signs of toxicity.  Since then, Chowdhury and colleagues have identified and validated TIRR as a new therapeutic target.   

“Activating p53 has been the holy grail of cancer drug discovery,” says Dr. Chowdhury. “If we can activate this powerful tumor suppressor without altering protein levels, we should be able to suppress a wide variety of tumors. We are cautiously optimistic that TIRR inhibitors will upregulate p53 without toxicity.”  

Accelerator funding will help the team make chemical compounds targeting TIRR. Already, multiple hits for chemical matter have been identified through small molecule library screens and the team is optimizing the chemical starting points into potent and selective TIRR inhibitors. 

Team Members