Modeling anticancer drugs on the pathway JAK-STAT in cancer stem cells

In mammals, the JAK / STAT pathway is the major signaling mechanism for a wide range of cytokines andgrowth factors [۱,۲]. Many recent studies show that inhibition of STAT۳ in various tumor cells has anticancereffects. In this paper, the functional regions of STAT۳ were analyzed and structures with PDB codes ۴E۶۸-A, ۱BG۱-A, ۳CWG-A, ۱YVL-A, ۱BF۵-A, ۴ZIA-A and ۱Y۱U-A were selected to generate homologymodels. Water, ligands, and additional chains of these structures were removed using Chimera ۱.۸ softwarefor modeling with Modeler ۹. ProSA-website and Rampage were used to confirm the accuracy of themodeling. STAT Inhibitors FLLL۳۲, HJC۰۱۲۳, STX-۰۱۱۹, LLL۱۲, INS۳-۵۴, and Piperlongumin werecreated using MarvinSketch software and minimized using Hyperchem software. The compounds Stattic andSta-۲۱ were obtained from PubChem. Molecular docking was performed using AutoDock tools and evaluatedafter ۱۰۰ runs. This study showed that despite the explanation of some articles regarding the inhibitory effectof compounds HJC۰۱۲۳, Ins۳۵۴, Sta-۲۱, and Statiic on the DNA-binding domain, Ins۳۵۴ appears to bindmore strongly to DNA by binding to arg۴۳۲ and lys۵۷۴ than the other compounds (-۰.۲۶; -۸.۲۹). Amongthese compounds, Statiic appears to bind to both the DNA-binding domain and the SH۲ domain with greaterstability, inhibiting dermirization and DNA binding. By inhibiting these processes, transcription of the geneis inhibited and the cancer cell can no longer replicate and continue to grow. Since the drugs Ins۳۵۴ and Sta-۲۱ have the same inhibitory effect, it is expected that taking two drugs at the same time will lead to acompetitive situation and the inhibitory effect will not be different from the indicated amount, but may beworse due to the side effects of the two drugs. However, taking one of these two drugs in combination withStatiic may increase the inhibitory effect.