Abstract A158: Development of CYP26 inhibitors to optimize the treatment of neuroblastoma with retinoic acid

Abstract

Abstract Neuroblastoma is the most common extra-cranial malignant solid tumor of childhood. It is diagnosed in approximately 800 children per annum in the USA, and currently has a poor prognosis for high-risk patients. Neuroblastoma treatment is limited by the development of resistance to retinoic acid (RA). Inhibition of CYP26, the enzyme primarily associated with RA-metabolism, has been demonstrated to enhance concentrations of RA both in vitro and in vivo. It is anticipated that these results may be translated into improved clinical therapy for neuroblastoma. We have designed, prepared and performed extensive in vitro testing of a small library of novel CYP26 inhibitors. A microsomal CYP26 inhibition assay was used to screen all novel inhibitors to generate initial IC50 values. The most promising compounds were further investigated in cellular assays, employing SH-SY5Y neuroblastoma cells, including proliferation assays and measurement of CYP26A1 mRNA induction, a sensitive biomarker reflecting intracellular RA concentrations. CYP selectivity assays have also been performed, providing data to assist in the selection of lead compounds that will have a reduced probability of possessing off-target effects on other CYP enzymes, a fundamental limitation in previous attempts to target CYP26. A number of compounds have exhibited impressive CYP26 inhibitory potency, with IC50 values <10 nM observed in microsomal assays. Co-incubation of SH-SY5Y cells with lead compounds and low levels of RA increased the level of expression of CYP26A1 mRNA up to 30-fold, relative to SH-SY5Y cells treated with RA alone. This potentiation reflects the ability of these novel inhibitors to enhance and prolong the in vitro effects of RA. Our research program has generated a number of highly potent CYP26 inhibitors to be tested in vivo. It is anticipated that these studies will lead to the generation of compounds which may be used in combination with RA to improve the future treatment of neuroblastoma. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A158.