Structural solution

The poison arsenic is a well-worn device of crime novels. But in low doses it can also be a useful treatment for acute promyelocytic leukemia. Building on the latter theme, a study led by Ludwig Oxford Director Xin Lu and Min Lu of the Shanghai Institute of Hematology performed a screen for drugs that could reactivate mutant forms of the p53 tumor suppressor and found that arsenic compounds—including arsenic trioxide—rescued some structural defects in p53. Although p53, called the “guardian of the genome,” is the most frequently mutated gene in human cancer, efforts to devise drugs that reactivate the mutated protein have generally come up short. This is due to the large variety of p53 mutations, their diverse effects and a lack of sites on the p53 protein that can be easily targeted by drugs. However, over half of all p53 mutations cause structural alterations that affect p53 activity. These mutants were the focus of the study reported in Cancer Cell in December. For some of the structural mutations, arsenic trioxide was also able to reactivate the tumor suppressor function of p53 in experimental models. It is now being tested in a phase I clinical trial in patients with p53-mutated blood cancers.

This article appeared in the April 2021 issue of Ludwig Link. Click here to download a PDF (1.4 MB).


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