Development of CYP26 Inhibitors as Neuroblastoma Therapeutics
Introduction
Retinoic acid (RA), the active metabolite of vitamin A, binds with nuclear receptors RAR/RXR to regulate cell growth and differentiation in a variety of cell types, and can reverse malignant growth in vitro and in vivo. These properties have led to RA being used effectively in a number of clinical situations including acute promyelocytic leukaemia (APL) and neuroblastoma.
Neuroblastoma is an embryonal neoplasm and other than brain tumours, it is the most common solid tumour of childhood, currently responsible for the highest number of cancer-related deaths in pre-school age children. Approximately 100 children develop neuroblastoma each year in the UK and most of these are less than 4 years of age. The cure rates, especially for stage 3 and 4 disease, remain low but the most significant improvement in treatment of high-risk neuroblastoma in recent years has come from the use of 13cisRA after myeloablative therapy.
Despite the promising initial clinical impact of retinoic acid (RA) therapy in high-risk neuroblastoma, with an observed increase in 3 year event-free survival of 17%, the majority of children still relapse within three years owing to development of drug resistance associated with RA metabolism. The main route of RA metabolism, likely to represent the main negative feedback control of intracellular RA concentrations, is via a family of RA-inducible P450s, P450RAI or CYP26.
Interaction of tetralone inhibitor with the CYP26A1 active site
Aims of Project
Inhibitors of CYP26 are expected to limit oxidative metabolism, thereby enhancing endogenous levels of the active parent drug. We have developed potent CYP26 inhibitors, which display comparable activity with R116010 when combined with RA in antiproliferative assays, and improved activity versus R116010 with respect to inhibition of ATRA metabolism and induction of CYP26A1 mRNA. The current proposal builds upon our productive collaboration with the Northern Research Institute, incorporating optimisation of inhibitor design and synthesis, CYP26 inhibitory activity and CYP selectivity alongside a full evaluation of antiproliferative properties, ability to induce gene expression (CYP26 and RAR*) and cytotoxicity. Development of an animal model will allow in vivo evaluation of pharmacokinetics and toxicity/efficacy of selected lead compounds.
Funder
Cancer Research UK
Project Value
£109,646
Duration
2 years
Additional Information
Additional information about cyp26 inhibitors is available on Claire Simons' personal web site.
The project, funded by Cancer Research UK (Discovery Committee), will support two postdoctoral research associates, one based at the Welsh School of Pharmacy -Dr Claire Simons and Dr Andrea Brancale - (drug design & synthesis) and one at the Northern Cancer Research Institute - Dr Jane Armstrong, Dr Chris Redfern and Dr Gareth Veal - (biological evaluation).
