Toxicity Risk Reduced For Isothiazole Drug

Researchers at biopharmaceutical firm Amgen have discovered a potential toxicity mechanism of a promising isothiazole-containing anticancer drug, and they have used the information to modify the drug to avoid the toxicity without altering its medicinal properties (Chem. Res. Toxicol., DOI: 10.1021/tx100208k). This development serves as a “structural alert for medicinal chemists who might consider using a methyl isothiazole group to increase potency or improve pharmacokinetics,” Yohannes Teffera and coworkers note. The drug is a potent, selective inhibitor of c-Met, a receptor tyrosine kinase enzyme that gets out of control in cancer. The methyl isothiazole group is normally safe, but in preclinical studies the team found that the drug forms a conjugate with the antioxidant tripeptide glutathione, indicating that the drug is bioactivated in the liver—the first step toward drug toxicity. The researchers uncovered a previously unknown bioactivation mechanism for isothiazoles in which the sulfur atom is oxidized via a P450 enzyme, thereby leaving a ring carbon susceptible to nucleophilic attack by glutathione. They subsequently prepared isoxazole and pyrazole analogs of the drug, which have oxygen and nitrogen, respectively, in place of sulfur. These analogs aren’t susceptible to bioactivation and avoid toxicity without affecting the drug’s efficacy.