Novel 3,6-Disubstituted\nPyridazine Derivatives Targeting\nJNK1 Pathway: Scaffold Hopping and Hybridization-Based Design, Synthesis,\nMolecular Modeling, and <i>In Vitro</i> and <i>In Vivo</i> Anticancer Evaluation

A series of novel 3,6-disubstituted pyridazine derivatives\nwere\ndesigned, synthesized, and biologically evaluated as preclinical anticancer\ncandidates. Compound <b>9e</b> exhibited the highest growth\ninhibition against most of the NCI-60 cancer cell lines. The <i>in vivo</i> anticancer activity of <b>9e</b> was subsequently\ninvestigated at two dose levels using the Ehrlich ascites carcinoma\nsolid tumor animal model, where a reduction in the mean tumor volume\nallied with necrosis induction was reported without any signs of toxicity\nin the treated groups. Interestingly, compound <b>9e</b> was\ncapable of downregulating c-jun N-terminal kinase-1 (JNK1) gene expression\nand curbing the protein levels of its phosphorylated form, in parallel\nwith a reduction in its downstream targets, namely, c-Jun and c-Fos\nin tumors, along with restoring p53 activity. Furthermore, molecular\ndocking and dynamics simulations were carried out to predict the binding\nmode of <b>9e</b> and prove its stability in the JNK1 binding\npocket.