Design, synthesis, and biological evaluation of SMYD3 inhibitors possessing N-thiazole benzenesulfonamide moiety as potential anti-cancer agents

Background: SMYD3 is a protein lysine methyltransferase that methylates lysine in histone and non-histone proteins resulting in regulation of gene transcription and cell signaling pathways. It has been established that SMYD3 enzyme is upregulated in different types of cancers such as breast, gastric, pancreatic, colorectal, lung cancer, and hepatocellular carcinoma. Therefore, inhibition of SMYD3 enzyme in cancerous cells represents a novel therapeutic strategy in cancer treatment. Efforts to identify small molecule inhibitors of the SMYD3 catalytic function had resulted in the discovery of few inhibitors that have been reported in the literature. Methods: Based on the preliminary in vitro results of two pilot compounds against SMYD3 enzyme, a series of N-thiazole benzenesulfonamide derivatives were designed, synthesized, and biologically evaluated against SMYD3 enzyme. Further, molecular docking and molecular dynamics (MD) simulations were conducted to provide an insight for the binding interactions of the synthesized compounds with SMYD3 enzyme. Results and conclusions: The in vitro methyltransferase inhibitory assays of the synthesized compounds revealed a prominent enhancement in SMYD3 inhibition with the most active compound (SA6) showed more than seven-fold enhancement in SMYD3 inhibition with an IC50 value of 6.21 ± 1.35 µM compared to the hit compound. Based on the biological results, a primary SAR analysis of the synthesized series was proposed. Moreover, molecular docking and molecular dynamics (MD) simulations revealed that compound SA6 has a favorable binding affinity towards the substrate-binding pocket of the SMYD3 enzyme with a unique binding mode. This unique binding mode of SA6 can be utilized to advance the design of analogs with higher SMYD3 binding affinity, eventually enhancing their inhibitory activity.