Novel Class of Small Molecules Restores Important p53 Pathway
Approximately 50% of human cancers involve mutations in the tumor-suppressor gene p53, while the other 50% involve some type of inactivation on the p53 pathway. We have discovered a class of small molecules that restore the p53 pathway, as well as perturb an S-phase checkpoint.
There are currently no FDA-approved drugs to restore the p53 pathway. Existing drugs are limited to ones that restore the mutant to wild-type p53 conformation, HSP90 inhibitors that target the mutant p53 protein for degradation, and MDM2 inhibitors that facilitate wild-type p53 activation.
Innovation and Meaningful Advantages:
Instead of directly targeting p53, we took a new approach and screened for small molecules that restore the p53 pathway. The screening identified a new subclass of xanthine compounds that are much more potent in their cytotoxic effects than other xanthines, such as caffeine, pentoxifylline, and theophylline. They also perturb the S-phase checkpoint. This combination of p53 pathway-restoration and S phase-perturbation is unique to this subclass of xanthines.
Commercial Development: Current State and Next Steps:
We are studying applications of this class of p53 pathway-restoring drugs in cancer treatments, such as combination therapies with chemotherapy agents for cancers with BRCA1/2 mutations, as well as combination therapies with PARP inhibitors. We are also investigating new therapy regimens for synthetic lethality, in which mutations in a cancer gene are associated with other vulnerabilities that could be targeted.
Our goal is to collaborate with biopharma partners who can bring into play the developmental, translational, and financial resources needed to advance this technology through regulatory approval and into the commercial marketplace.
Wafik El-Deiry, MD, PhD
Minkoff Family University Professor of Medical Science
Professor of Pathology and Laboratory Medicine
Brown Tech ID #3049
PCT/US2021/032770, published November 18, 2021.
Chen F, et al., Current strategies to target p53 in cancer. Biochemical Pharmacology. 80(5): 724-730.
Wang W, et al., Small-molecule modulators of p53 family signaling and antitumor effects in p53-deficient human colon tumor xenografts. Proceedings of the National Academy of Sciences. 103(29): 11003-11008
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