In vitro Metabolic Profiling for the Choice of Schweinfurthin Analog Development Candidate

Introduction: The schweinfurthin class of compounds has been under investigation for two decades as potential cancer treatment candidates. Recent work demonstrating that these agents can induce immunogenic cell death has led to increased interest in our lab in establishing a development candidate. Methods: Here we use microsomal stability studies and reaction profiling of CYP450s involved in the metabolism of the two compounds 5’-methylschweinfurthin G (MeSG, TTI-3114) and TTI-4242, as well as CYP450 induction using cell culture in HepaRG cells. Results: TTI-4242 is more stable to microsomal enzymes than MeSG. CYP3A4 is primarily responsible, with some contributions from CYP2D6, CYP2C9, CYP2C19, and CYP1A2. In addition, both compounds induce the activity of CYP2D6. Discussion: Here we set out to determine the initial metabolic disposition of two of the most advanced schweinfurthin compounds, focusing on reaction profiling and cytochrome P450 (CYP450) induction, to help choose which of these should have more resources devoted to chemical synthesis and in vivo testing. Conclusion: The results from this study have led us to focus our resources on the indole-containing schweinfurthin analog TTI-4242 for further development as a treatment for melanoma and other cancers.