Exploitation of dihydroorotate dehydrogenase (DHODH) and p53 activation as therapeutic targets: A case study in polypharmacology [Computational Biology]

In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo 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.

Source: Journal of Biological Chemistry - December 25, 2020 Category: Chemistry Authors: Marcus J. G. W. Ladds, Gergana Popova, Andres Pastor–Fernandez, Srinivasaraghavan Kannan, Ingeborg M. M. van Leeuwen, Maria Hakansson, Bȷorn Walse, Fredrik Tholander, Ravi Bhatia, Chandra S. Verma, David P. Lane, Sonia Lain Tags: Cell Biology Source Type: research