Postdoctoral scholar Dr. Dmytro Havrylyuk received an award for the poster “Ru(II) CYP1B1 Inhibitor Prodrugs with Enhanced Potency” at the 2018 Metals in Medicine, Gordon Research Conference. The project was performed in collaboration with Kimberly Stevens and Catherine A. Denning in the laboratories of Dr. David K. Heidary and Prof. Edith C. Glazer
Dr. Havrylyuk described the development of highly potent and selective inhibitors of Cytochrome P450 1B1 (CYP1B1), an enzyme that is involved in cancer initiation, progression, and resistance to treatment. CYP1B1 is overexpressed in a wide variety of human tumors, giving it the title of “universal tumor antigen”. The enzyme catalyzes the 4-hydroxylation of 17β-estradiol to form a 3,4-quinone, which reacts with DNA, inducing mutation. CYP1B1 is also implicated in cancer progression by enhancing cell proliferation, inducing cell cycle transition, and inhibiting cellular apoptosis. Importantly, CYP1B1 expression results in resistance to various chemotherapeutics with different mechanisms of action. As a result, CYP1B1 is a promising therapeutic target for both chemoprevention and combination chemotherapy by reducing drug-resistance.
Dr. Havrylyuk designed and evaluated a library of potential inhibitors of CYP1B1, and the compounds were tested in innovative live cell assay, developed by Dr. Heidary. The most selective inhibitors possessed inhibitory effects on CYP1B1 at picomolar concentrations and exhibited selectivity of over 100,000-fold compared to human liver CYPs. The compounds were non-toxic, and exhibited excellent cellular uptake. Dr. Havrylyuk also developed Ru(II) complexes as CYP1B1 prodrugs for the photoinduced delivery of CYP1B1 inhibitors. In addition to presenting the results of the project in the poster session, Dr. Havrylyuk was honored to be chosen to highlight the project in a short oral presentation.