Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense

Area of Science:

• Natural Products Chemistry
• Medicinal Chemistry
• Cancer Biology

Background:

• Cancer cells exhibit heightened dependence on MTH1 (NUDT1) due to redox dysregulation.
• MTH1 is crucial for tumor cell survival but not essential for normal cell growth, making it a promising anti-cancer target.
• Farnesyl phenols with coumaroyl substitution are rare natural products.

Purpose of the Study:

• To isolate and characterize novel farnesyl phenolic compounds from Ganoderma sinense.
• To evaluate the potential of these compounds as MTH1 inhibitors for cancer therapy.
• To confirm the selective binding of these compounds to MTH1 in cancer cells.

Main Methods:

• Isolation and structural elucidation of compounds using HPLC, spectroscopic analyses (NMR, MS), and ECD.
• Virtual ligand screening to predict MTH1 binding affinity.
• Enzyme inhibition assays, cell-based assays, siRNA knockdown, and CETSA to confirm MTH1 inhibition and specificity.
• Cytotoxicity assays on normal human cells.

Main Results:

• Eight farnesyl phenolic compounds, including six new ganosinensols E-J, were isolated.
• Compounds showed predicted high binding affinity to MTH1.
• Enzyme and cell-based assays confirmed MTH1 inhibitory effects.
• Specific binding to MTH1 in intact cells was confirmed by siRNA and CETSA.
• Compounds exhibited low cytotoxicity against normal human cells, indicating good selectivity.

Conclusions:

• Novel farnesyl phenolic enantiomers from Ganoderma sinense effectively inhibit MTH1.
• These compounds demonstrate high selectivity for MTH1 in cancer cells over normal cells.
• The identified compounds represent promising lead structures for developing targeted anti-cancer therapeutics.