A) Novel mechanism of action: a short exposure to ZMCs increases zinc levels in tumors enough to restore normal structure/function to mutant p53 which leads to p53 mediated cancer cell death. B) Novel formulation: Synthesizing ZMCs as a zinc-loaded complex (Zn-1) improves survival in a pancreatic cancer mouse model compared to the ZMC compound alone.
More than half of all cancers harbor a mutation in the p53 gene which plays an essential role as a tumor suppressor. Restoring wild type p53 function has been shown to have potent anti-cancer activity and also improves the efficacy of chemotherapy and radiation treatment. Given the large number of cancer patients with p53 mutations, restoring the wild type structure and function of mutant p53 is a highly sought after goal in the development of cancer therapeutics.
Rutgers scientists have developed a new class of mutant p53 reactivators called zinc metallochaperones (ZMCs). ZMCs have been identified as a novel approach for targeting specific p53 mutants with impaired zinc-binding by raising cellular zinc levels sufficiently to restore normal p53 structure/function and induce p53-mediated cancer cell death. This novel mechanism occurs quickly (within minutes) and is irreversible, so drug exposure time is minimal which reduces the potential for toxicity. Pre-clinical evidence in multiple models of breast, pancreatic, and ovarian cancer show that ZMC therapy is highly efficacious and specific for zinc-deficient mutant p53 tumors. Synthesizing ZMCs in complex with zinc is a novel formulation that improves efficacy over ZMCs alone. These ZMC-Zinc complexes have better drug-like properties (potency, solubility) to serve as pharmacologic lead molecules.
- Targeted anti-cancer drugs
- Combination therapy with conventional cancer treatments
- Only brief ZMC exposure (<30 mins) is necessary for massive cancer cell death
- ZMC complexes are rapidly cleared in vivo
- New ZMC complexes have improved potency and lower toxicity
Intellectual Property & Development Status:
Multiple issued patents and pending patent applications. Available for licensing and/or research collaboration.
- Na et al., NPJ Breast Cancer 2019 Apr 15: 5:14
- Yu et al., Clin Cancer Res. 2018 24(18): 4505-451
- Yu et al., Mol Pharmacol. 2017 91(6): 567-575