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

Abstract

Aspartate transcarbamoylase (ATC) is a key enzyme involved in pyrimidine biosynthesis and is required for the proliferation of parasites and cancer cells. 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, mainly focusing on reporting a previously unreported allosteric pocket, which reveals an allosteric mechanism of inhibition. This allosteric pocket greatly enhances the drug ability of ATC and represents an attractive target for the development of new ATC inhibitors for anti-malaria or cancer therapy.