DHODH, a likely target for small molecules activating p53

In this lecture I will discuss how a knowledge-based approach can lead to elucidating cellular targets for small molecules with anticancer activity. This deductive strategy is of particular relevance when the target is not abundant and is membrane bound. In the recent past we have demonstrated that a series of bioactive compounds identified in our lab directly inhibit dihydroorotate dehydrogenase (DHODH). According to our model, cells rapidly sense deficiencies in pyrimidine-nucleotide levels and/or respiratory chain activity through DHODH to protect the genome, and do so by altering key nuclear functions. In addition, these studies suggest indicators for sensitivity of certain cell lines to DHODH inhibitors.