A new class of Indole-based HDAC8 inhibitors as potential anti-lung cancer agents: In silico design, synthesis, biological assessment and binding interaction analysis

Abstract

A novel series of indole-based hydroxamic acids was designed, synthesized, and evaluated as promising HDAC8 inhibitors for lung cancer therapy. In silico analyses, including classification-based QSAR, chemical space networks, and scaffold diversity analysis on 2078 HDAC8 inhibitors uncovered essential molecular features for strong HDAC8 potency, informing the design of 12 derivatives. Docking studies ranked the top two candidates, which were subsequently derivatized, synthesized and evaluated through HDAC8 enzymatic and cytotoxicity assays. Several compounds proved highly active, with 6c exhibiting superior HDAC8 inhibition, strong antiproliferative activity against A549 cells, and minimal impact on HEK-293 normal cells. Mechanistic studies demonstrated apoptosis induction, G2/M arrest, ROS generation, and increased nuclear fragmentation. Western blot analysis confirmed intracellular HDAC8 inhibition through elevated SMC3 acetylation, while 500 ns molecular dynamics simulations supported stable binding of 6c within the HDAC8 active site. Collectively, these findings identify compound 6c as a promising HDAC8 inhibitor and potential lead candidate for the development of novel anti-lung cancer agents targeting epigenetic pathways. This work provides insights that might advance efforts to develop effective non-platinum anticancer agents.