PhD defence C. (Chao) Wang

Allosteric inhibitors of aspartate transcarbamoylase: targeting pyrimidine biosynthesis to address multiple diseases

Pyrimidine nucleotides play a critical role in all living organisms and are essential for the synthesis of DNA, RNA, and other crucial cofactors. There are two pyrimidine synthesis pathways: a salvage pathway and a de novo pathway. While the degree of pyrimidine synthesis is highly dependent on both the type and stage of cells, in general, nondividing and slowly dividing cells rely on salvage pathways that use nucleosides derived from the hydrolysis of nucleic acids to support survival. However, the salvage pathway cannot satisfy the continuous demand for nucleic acids in proliferating cells, which then become dependent on de novo synthesis. For instance, the activity of the de novo pathway is upregulated in cancer cells and blood-stage Plasmodium parasites. Aspartate transcarbamoylase (ATC) catalyzes the second step of pyrimidine biosynthesis, and chemicals blocking ATC function would be valuable for anti-malaria drug development and cancer therapy. In this thesis, we detail the discovery of a class of small-molecule allosteric inhibitors of ATCs, termed the BDA series, targeting a previously unreported allosteric pocket, which reveals an allosteric mechanism of inhibition. This allosteric pocket greatly enhances the druggability of ATC and represents an attractive target for the development of new ATC inhibitors for anti-malaria and cancer therapy.

Promotors: Prof.dr. M.R. Groves