Development of small molecule NUDT22 inhibitors for uses in cancer.

Abstract

Here we present the characterisation of the so far unstudied NUDIX hydrolase family member NUDT22. We previously identified a unique hydrolase activity of NUDT22 towards UDP-glucose from a family-wide biochemical substrate screen. UDP-glucose hydrolysis results in the production of uridine monophosphate (UMP) and glucose 1-phosphate (G-1-P). We furthermore solved the first crystal structure of NUDT22 in complex with its substrate UDP-glucose [1]. Our mechanistic studies reveal increased replication stress in NUDT22 deficient cells which can be rescued by nucleoside supplementation. We therefore propose the discovery of a novel NUDT22-mediated pyrimidine salvage pathway.Increased replication rates resulting in replication stress is a hallmark of cancer cells and NUDT22 gene expression alterations are present in several cancer tissues, which makes it an interesting new target for the development of small molecule inhibitors for uses in cancer.We employed our NUDT22 crystal structure to perform an in silico docking screen on available small molecule libraries to identify starting points for the development of first-in-class NUDT22 inhibitors. Chemically optimised NUDT22 inhibitors are currently being validated in biochemical assays, cellular target engagement assays, and their cellular activity is being assessed in vitro. [1] M. Carter et al., "Human NUDT22 Is a UDP-Glucose/Galactose Hydrolase Exhibiting a Unique Structural Fold," Structure, vol. 26, no. 2, pp. 295-+, Feb 2018, doi: 10.1016/j.str.2018.01.004.