Targeting SUMOylation with Anacardic Acid Derivatives: Novel Insights into EGF Pathway Dysregulation in Cancer Using...

SUMOylation is a critical post-translational modification pathway implicated in various ailments, such as diabetes, neurodegenerative disorders, infectious diseases, and cancer. Dysregulation of SUMOylation affects different hallmarks of cancer, including metastasis, angiogenesis, invasion, and proliferation, making it an important therapeutic target. While anacardic acid (AA) has been shown to inhibit the essential SUMO E1 enzyme (IC50 = 2.1 μM), its clinical potential is limited by high lipophilicity and poor bioavailability, stemming primarily from its C15 alkyl chain. This study is therefore aimed at identifying AA derivatives with improved druggability. Using Mcule, 129 AA derivatives were generated and subjected to molecular docking against SUMO E1, which yielded 61 potential inhibitors based on binding energy. Subsequent virtual screening with SwissADME evaluated their pharmacokinetic properties (solubility, logP, and toxicity), narrowing the candidates to 24 hits. Further analysis identified 2-hydroxy-6-methylbenzoic acid as the top lead compound, demonstrating a superior pharmacokinetic profile. Molecular dynamics simulation studies confirmed its stable binding to SUMO E1 through favorable hydrogen bonding. Previous studies from our laboratory have shown AA to regulate the EGF pathway by inhibiting MMPs directly as well as through its modulators, BSG and TIMP. Based on these observations, GPS SUMO analysis demonstrated potential SUMOylation sites in both BSG and TIMP, which have the potential to be modulated by the lead compound, resulting in regulation of the EGF pathway, thereby controlling cancer progression. These observations strongly support the development of 2-hydroxy-6-methylbenzoic acid and its analogues as potent SUMO E1 inhibitors with enhanced pharmacokinetic profiles for cancer therapy.