In silico discovery of a novel potential allosteric PI3Kα inhibitor incorporating 2-oxopropyl urea targeting head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the most common head and neck cancer and highly aggressive and heterogeneous. Targeted therapy is still the main treatment method used in clinic due to lower side effect and personalized medication. In order to discover novel and effective drugs with low side effect against HNSCC, we analyzed the genes related to HNSCC, and found that PIK3CA was highly expressed in tumor tissues and often experienced mutations, leading to excessive activation of phosphoinositide 3-kinase alpha (PI3Kα), promoting the development of HNSCC. The allosteric PI3Kα inhibitor STX-478 inhibits the growth of tumor with hotspot mutations in PI3Kα and shows prominent efficacy on the treatment of human HNSCC xenografts without displaying the metabolic dysfunction observed in Alpelisib. These mutations open the allosteric site more readily, increasing the selectivity of STX-478 for mutant PI3Kα. STX-478 cleverly avoids the side effect of ATP competitive PI3Kα inhibitors. So, the structure of STX-478 was optimized based on the interaction mechanism between STX-478 and PI3Kα. Then, virtual screening, binding mode research, target verification, physical and chemical properties, pharmacokinetic properties and stabilities of ligand-PI3Kα complexes were evaluated by computer technologies (scaffold hopping, cdocker, SuperPred, SwissTarget prediction, Lipinski's rule of five, ADMET and MD simulation). Finally, J-53 (2-oxopropyl urea compound) with excellent properties was selected. J-53 not only formed H-bonds with key amino acids, but its unique -C(O)CH₃ could also form H-bonds with ILE1019, making it more stably bound to PI3Kα and contributing to its activity. After the SciFinder verification, J-53 with novel structure had the value of further study. This study suggested that J-53 could be used as potential inhibitors of PI3Kα, and provides valuable information for the subsequent drug discovery of allosteric PI3Kα inhibitors.