Mechanism of action: Inhibitor of the enzyme MTH1; NUDT1 nudix hydrolase 1

Preclinical pharmacology

AZ13792138 is a potent, reversible, nucleotide competitive inhibitor of the MTH1 enzyme.  It has an enzyme IC50 of 0.5 nM.  Engagement of the MTH1 target in cells has been demonstrated using a whole cell thermal stability assay (CETSA) where the compound has an EC50 of 3 nM.  It has a measured affinity for MTH1, Kd = 0.4 nM with a long residence time (half life) for binding to the protein of 81 minutes.

Safety and tolerability

The safety and tolerability of this agent is not known. It has been dosed in a low dose Rat pharmacokinetics study using the vehicle for IV dosing of 5% DMSO 95% SBE-B-CD (30% w/v) in water, and for PO suspension dosing of 0.5% HPMC 0.1% TWEEN in water adjusted to pH3, at doses of 0.5 and 1.0 mg/kg respectively. In this study, AZ13792138 had a bioavailability of 64%, clearance of 26 ml/min/kg and a half life (po) of 1.7 h.

Additional Information

Publications for this compound

Find out more about this compound by reading related publications:

Journal of Medicinal Chemistry

Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival

Journal of Medicinal Chemistry

MutT Homolog 1 (MTH1): The Silencing of a Target

Gene information from the NCBi

This compound works on the following genes: