BAY-707

MTH1 is a hydrolase responsible for sanitization of oxidized purine nucleoside triphosphates to prevent their incorporation into replicating DNA. Early tool compounds published in the literature inhibited the enzymatic activity of MTH1 and subsequently induced cancer cell death; however recent studies have questioned the reported link between these two events. Therefore, it is important to validate MTH1 as a cancer dependency with high quality chemical probes. Here, we present BAY-707, a substrate-competitive, highly potent and selective inhibitor of MTH1, chemically distinct compared to those previously published. Despite superior cellular target engagement and pharmacokinetic properties, inhibition of MTH1 with BAY-707 resulted in a clear lack of in vitro or in vivo anticancer efficacy either in mono- or in combination therapies. Therefore, we conclude that MTH1 is dispensable for cancer cell survival.

A series of novel derivatives of 3-(arylamino) quinazoline-2,4(1 H ,3 H )-dione were synthesized with moderate to good yields (20%−70%) using t -butyl hydroperoxide (TBHP) and iodine. Their efficacy against MutT homologue 1 (MTH1) was evaluated using in silico methods. Density functional theory (DFT) analysis, utilizing the B3LYP/6-311G (2df, p) basis set, indicated a promising reactivity profile for the synthesized compounds. The highest occupied molecular orbital (HOMO) regions associated with the phenylhydrazine group serve as sites for electron donation, functioning as electron-rich nucleophiles. Docking analysis with MTH1 enzymes revealed that all compounds exhibited docking scores ranging from −5.77 to −7.24, indicating favorable binding affinities. Among these, compound (3d) , with an energy of −7.24 kcal/mol, demonstrated the strongest binding affinity. Importantly, the Generalized Born and Surface Area Solvation (MM-GBSA) rescoring aligned with the docking data, reinforcing the reliability of the predicted binding modes and highlighting these compounds as promising MTH1 inhibitors. Molecular dynamics (MD) simulations indicated that Tyr7, Thr8, Lys23, and Trp117 exhibited a notably high interaction fraction, suggesting that these residues might be critical for the binding affinity of compound (3d) . The analysis of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties indicated that all compounds possess a favorable pharmacological profile and comply with Lipinski’s Rule of Five (Ro5), as well as the Ghose, Veber, and Egan rules. Additionally, they are capable of human intestinal absorption (HIA) and exhibit no liver toxicity, whereas BAY-707 is anticipated to exhibit hepatotoxicity.