Phortress molecule.

Benzothiazole (NSC 674495)
Phortress (NSC 710305)

Work by Dr. Malcolm Stevens of the Cancer Research UK Group at Nottingham University showed the potential of benzothiazole (NSC 674495) and related compounds as anticancer agents. Phortress (NSC 710305) is the lead compound from this work. This agent has demonstrated activity against breast tumors, regardless of estrogen receptor status, and against ovarian, renal, lung, and colon cancer cells.¹

Phortress has a unique mechanism of action: the active component binds to cytoplasmic arylhydrocarbon receptors and is taken to the nucleus, where it induces its own activation through the cytochrome p450 enzyme 1A1. The resulting intermediate species form DNA adducts that lead to cell death.¹

1994–1999 DTP initially received the benzothiazole parent compound in 1994, and a group of five benzothiazoles were presented to the Drug Development Group (DDG) in 1996. However, solubility of these compounds was poor. This drawback was overcome by the synthesis of the lysyl prodrug, Phortress, by Dr. Stevens, which DTP received in 1999.

2002 In 2002, DDG approved the development of Phortress as a clinical candidate and provided synthesis, formulation, pharmacokinetic, and toxicity resources.²

When lung toxicity was shown to be an issue, function studies were performed. The results of these pulmonary function studies did not show clear distinctions between control, low-dose, and high-dose animals. Other study results indicated that an alternative was to monitor hepatotoxicity as a surrogate for pulmonary toxicity.

2004 In July 2004, Pharminox obtained the exclusive right to develop and commercialize Phortress and its analogs.¹ The drug is undergoing phase I clinical trials in the United Kingdom to establish its safety, pharmacokinetic, and pharmacodynamic profile in cancer patients. Conduct of phase I trials in the United States await the results of the U.K. studies.

¹ Pharminox. Pharminox Product Pipeline: Phortress Overview.

² NCI Office of International Affairs. Clinical Trials and Preclinical Drug Development.

Link:

DTP aminoflavone/Phortress go-no go poster (pdf)

Phortress is similar to aminoflavone in mechanism of action, formulation for intravenous use, synthetic accessibility, and pharmacodynamics. Yet animal studies also show that these compounds may cause lung toxicity. Although pulmonary function studies clearly demonstrated the utility of pulmonary function testing to monitor patients given aminoflavone, results were less clear for Phortress. The drug is in clinical trials in the United Kingdom.