Developing Zinc Metallochaperones as Mutant p53 targeted Anti-Cancer Drugs
The gene that encodes the transcription factor, p53 (TP53) is the most commonly mutated gene in human cancer for which no effective targeted anti-cancer drug exists. The majority of mutations in p53 are missense, which means that a single amino acid change produces a defective protein which can serve as a target for cancer drug development. Genetic studies in mouse cancer models have revealed that restoring the function of p53 in cancer is highly therapeutic. The search for a small molecule that can restore the wild type structure and function to mutant p53 (so-called mutant reactivation) has been one of cancer drug development’s “holy grails”. Our laboratory discovered one of the first bonafide mutant p53 reactivators, ZMC1 (zinc metallochaperone-1) (PMID: 22624712) in 2012. The paper was featured in Nature, Nature Reviews Drug Discovery and Cancer Discovery for its significance. We named these small molecules - Zinc Metallochaperones (ZMCs) once we discovered their mechanism of action.
Like many transcription factors, p53 requires the binding of a single zinc molecule for proper structure. In fact, mutations that impair the protein’s ability to bind zinc are common mechanism that inactivates p53 in cancer. ZMC’s reactivate specific p53 mutants with impaired zinc binding by binding zinc and delivering it to the cancer cell to allow zinc to bind to mutant p53 and reactivate it. Once, mutant p53 is reactivated, it will kill the cancer cell. The Carpizo laboratory leads a multi-disciplinary team of investigators that range from molecular/cell biologists, to biophysical/biochemical scientists (Dr. Stewart Loh lab, Upstate Medical Center), to medicinal chemists (Dr. Jaques Roberge lab, Rutgers University). Our goal is to take our research on ZMC’s move this to the clinic. We currently have 8 patents that have resulted from this research and most recently a biotech company was created (Z53 Therapeutics Inc.) to commercialize this technology. This project is currently funded by the NIH (R01 CA200800).
The "switch" concept for the function of ZMCs in cacner drug development. With as little as 30 minutes of ZMC therapy, the switch is turned ON and an irreversible cascade of events is initiated in a cancer cell expressing a zinc deficient missense mutant p53. First, free zinc levels rise, then zinc becomes bound to the mutant p53 and induces a wild type conformation. This results in the induction of a wild type p53 mediated apoptotic program that results in cancer cell death. Cellular zinc homeostatic mechanisms then normalize the zinc levels, zinc is no longer bound to mutant p53 and the drug is OFF.
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