Recently, vitamin D, has been recognised as having anticancer activity. Analogues of calcitriol have enhanced anti-tumour activity, reducing the calcaemic effect. Selective inhibitors of CYP24A1, which metabolises and inactivates vitamin D, increase the lifetime and thereby the anti-cancer functions of calcitriol. The aim of this project is to develop new, potent and selective inhibitors of CYP24 in order to enhance the endogenous vitamin D levels and favour its anti-tumour activity.Through molecular modelling studies, the CYP24A1 active site has been characterised. Different series of potential inhibitors were designed in order to mimic completely the calcitriol disposition in the binding pocket and to interact with the haem iron of the enzyme catalytic site. For each of them a synthetic pathway was developed.The CYP24A1 inhibitory activity (IC50) and the value of the Ki (dissociation constant), compared with ketoconazole as the standard, were evaluated. New potent inhibitors were found.

Small molecule inhibitors of <i>CYP24A1</i> for treatment of various cancers

245th National Meeting (2013)

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Small molecule inhibitors of CYP24A1 for treatment of various cancers