Exploitation of dihydroorotate dehydrogenase (DHODH) and p53 activation as therapeutic targets: A case study in polypharmacology
Marcus J.G.W. Ladds, Gergana Popova, Andrés Pastor Fernández, Srinivasaraghavan Kannan, Ingeborg M.M. van Leeuwen, M. Håkansson, Björn Walse, Fredrik Tholander, Ravi Bhatia, Chandra Verma, David P. Lane, Sonia Laı́n
Abstract
pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.