In silico discovery of a novel potential allosteric PI3Kα inhibitor incorporating 2-oxopropyl urea targeting head and neck squamous cell carcinoma
Background: Head and neck squamous cell carcinoma (HNSCC) is the most common and aggressive type of head and neck cancer, characterized by high heterogeneity. Targeted therapy remains the primary treatment due to its ability to reduce side effects and provide personalized medication. To discover novel, effective, and low-side-effect drugs for HNSCC, we analyzed genes associated with the disease and identified PIK3CA, which is highly expressed and often mutated in tumor tissues. These mutations lead to the excessive activation of phosphoinositide 3-kinase alpha (PI3Kα), driving HNSCC progression.
Methods: We focused on the allosteric PI3Kα inhibitor STX-478, which targets PI3Kα mutations and inhibits tumor growth, particularly in tumors with hotspot mutations. STX-478 demonstrated significant efficacy in treating human HNSCC xenografts without the metabolic dysfunction observed with ATP-competitive PI3Kα inhibitors like Alpelisib. The allosteric site of PI3Kα, more accessible due to mutations, increases STX-478’s selectivity for the mutant form of PI3Kα. To optimize STX-478’s structure, we used computational methods, including virtual screening, binding mode analysis, target verification, and evaluation of the ligand-PI3Kα complex’s physical and chemical properties, pharmacokinetics, and stability.
Results: Through these techniques, we identified J-53 (a 2-oxopropyl urea compound) as a promising candidate. J-53 formed hydrogen bonds with key amino acids in PI3Kα, with its unique -C(O)CH3 group forming additional bonds with ILE1019, contributing to more stable binding and enhanced activity. SciFinder validation confirmed the novel structure of J-53, supporting its potential as an inhibitor of PI3Kα.
Conclusion: This study suggests that J-53 could serve as a potential inhibitor of PI3Kα, offering a new avenue for the development of allosteric PI3Kα inhibitors for HNSCC treatment. The findings provide valuable insights for future drug discovery efforts targeting PI3Kα in cancer therapy.