Repurposing <scp>FDA</scp>‐Approved Drugs to Target <scp>MTH1</scp> for Anticancer Therapeutics

Cancer cells exhibit elevated levels of reactive oxygen species, resulting in oxidative stress and DNA damage. To counteract this, many cancers upregulate the expression of MTH1 (MutT Homolog-1), a crucial enzyme that detoxifies oxidised nucleotide pools. Consequently, inhibiting MTH1 is a potential therapeutic strategy for managing DNA damage and cancer cell death. Here, we conducted a comprehensive computational screening of 3800 FDA-approved drugs to identify potential MTH1 inhibitors. Among these, Lumacaftor and Nilotinib were selected based on their strong binding affinity and pharmacokinetic profiles. Molecular dynamics simulations over 500 ns further validated the stable binding of these drugs to MTH1, suggesting their potential as effective inhibitors. Nilotinib, a well-known tyrosine kinase inhibitor (TKI), displayed strong binding affinity (Ka = 2.5 × 10⁴) and potent MTH1 inhibitory activity (IC₅₀: 37.2 μM). Notably, this study is the first to establish the interaction between Nilotinib and MTH1, highlighting the dual potential of Nilotinib as an MTH1 inhibitor. The findings suggest that Nilotinib could be repurposed to enhance cancer therapy, particularly in combating drug resistance through the novel mechanism of MTH1 inhibition. This approach provides new avenues for tackling chemoresistance and improving therapeutic outcomes in cancer patients.