In Silico Evaluation via Virtual Screening, ADMET Profiling and Molecular Dynamics Simulations: Synthesis and Biological Activity Analysis of a Novel Antitumor PI3K Inhibitor

The PI3K plays a crucial role in cancer progression, and the development of PI3K inhibitors has always been a hot research direction in oncology. Through virtual screening and docking, potential lead compounds were identified. ADMET prediction revealed that KTC101 possesses superior pharmacokinetic profile. Molecular dynamics simulations indicated that compound KTC101 could stably bind to PI3Kδ, with a binding free energy of −374.627 kJ/mol. Analysis of the metabolism of KTC101 revealed that this compound could undergo diverse phase I metabolic reactions catalyzed by hepatic CYP450 enzymes to form highly polar metabolites, indicating its strong metabolic potential and easy metabolic clearance in vivo. Then it was synthesized and evaluated for kinase inhibitory activity and antiproliferative effects in HNSCC cell lines. KTC101 was first reported as a PI3K inhibitor, with IC50 values of 191.23 ± 40.84 nM, 23.30 ± 5.68 nM, and 146.20 ± 21.82 nM for PI3Kα, PI3Kδ and PI3Kγ, respectively, and demonstrated dose-dependent inhibition of cancer cell growth in vitro, with IC50 values of 4.1 ± 0.73 μM for HSC3 cells and 2.2 ± 0.11 μM for HSC4 cells. It exhibited inhibitory activity against PI3K, showing greater inhibitory potency toward PI3Kδ. This study demonstrates the anti-tumor potential of KTC101.