Discovery of novel progesterone-heterocyclic conjugates and their encapsulated polymeric nanoparticles as potential CDK8 inhibitors: lung cytotoxicity evaluation, gene expression, and molecular docking

comparable to Cortistatin A (IV). Furthermore, compounds 4e and 4f CS-PEG nanoparticles significantly downregulated the CDK8, β-catenin, c-MYC, and HIF-1α genes as well as the protein expression levels of PI3K and AKT, and also upregulated the levels of P53 gene and MDA in A549 cells, thereby triggering ROS-mediated apoptosis and suppressing angiogenesis, invasion, and cell growth. Additionally, the molecular docking study confirmed that compounds 4e and 4f had a strong binding affinity to the active site of CDK8, consistent with their results and antiproliferative activity on A549 lung cancer cells.