Anthracycline prodrugs and methods of making and using the same
Patent Number: US8404650

Executive Summary:
  • Invention Type: Therapeutic
  • Patent Status: Granted
  • Patent Link: https://www.google.com/patents/WO2016176332
  • Research Institute: University of Colorado
  • Disease Focus: Leukemias, lymphomas, and solid tumors 
  • Basis of Invention: There is a need for improved anti-cancer prodrug compounds, based on the widely used, but highly toxic, doxorubicin molecule, that are effective, shelf stable and easily administered with improved cancer-targeting activities. Preferably, such anti-cancer compounds possess at least the anti-cancer efficacy of doxorubicin while eliminating, or substantially reducing, the associated cardiotoxicity and simultaneously overcoming the doxorubicin drug resistance displayed by many cancer cells. The foregoing disadvantages of the prior art anticancer compounds are overcome by the compounds and methods of this disclosure 
  • How it works: The present disclosure provides novel anticancer compounds, pharmaceutical compositions containing these compounds, as well as methods of making and using these novel compounds. To design improved anti-cancer prodrug compounds based on the highly toxic doxorubicin molecule that are effective, shelf stable, easily administered, and with improved cancer-targeting activities, the inventors utilized a photoactivation strategy that can activate a cytotoxic prodrug inside or near a cancer cell, and/or cells involved in the angiogenesis of the cancer cell. Important design criteria are selective delivery of photons of sufficient energy for the activation and the release of a highly cytotoxic drug that is relatively short lived. As described above, the clinical antitumor drug doxorubicin reacts reversibly with formaldehyde at the vicinal amino alcohol to give doxazolidine, which is at least an order of magnitude more toxic to both sensitive and resistant cancer cells than doxorubicin, and its toxicity stems from a different mechanism (doxorubicin is a topoisomerase 2 poison, leading to DNA double strand breaks; doxazolidine crosslinks DNA to induce cell death). However, due to aqueous instability, efficacious in vivo use of doxazolidine requires delivery as a prodrug where activation occurs at the site of the tumor. Thus, doxazolidine is an ideal candidate for prodrug release as it is short-lived and highly toxic (at 37 °C and pH 7.4, doxazolidine has a half-life of 3 min, during which the oxazolidine ring hydrolyzes, reforming doxorubicin).
  • Lead Challenge Inventor: Tad H. Koch
  • Inventors: Tad H. Koch, Benjamin L. Barthel, Hang Hubert YIN, Ryo Tamura, Alla Balabanova
  • Clinical Applications:
    • Chemotherapeutic drug

General Description:
  • The anthracycline anti-cancer drug, doxazolidine, is a formaldehyde-adduct of the clinically used chemotherapeutic, doxorubicin, which exhibits increased potency, orders of magnitude greater than doxorubicin, due to a change in the drug's mechanism of action. However, under physiological conditions, doxazolidine undergoes rapid hydrolysis to the parent dru and formaldehyde, which prevents direct administration in vivo and instead requires the use of a prodrug strategy. Therefore, there is a need for improved anti-cancer prodrug compounds based on the widely used but highly toxic doxorubicin molecule that are effective, shelf stable and easily administered with improved cancer-targeting activities. Preferably, such anti-cancer compounds possess at least the anti-cancer efficacy of doxorubicin while eliminating, or substantially reducing, the associated cardiotoxicity and simultaneously overcoming the doxorubicin drug resistance displayed by many cancer cells. The foregoing disadvantages of the prior art anticancer compounds are overcome by the compounds and methods of this disclosure.

Strengths:
  • Improved anti-cancer prodrug that is highly toxic and short-lived

Weaknesses:
  • Similar drugs on the market

Patent Status:
  • Publication date                 Nov 3, 2016
  • Filing date                          Apr 27, 2016
  • Priority date                       Apr 27, 2015

Inventor Bio: Tad H. Koch
http://www.colorado.edu/chembio/tad-koch