Modeling, synthesis and NMR characterization of novel chimera compounds targeting STAT3

Abstract

Chimera derivatives as potential STAT3 inhibitors.

Signal Transducer and Activator of Transcription Protein 3 (STAT3): An Update on its Direct Inhibitors as Promising Anticancer Agents

“…This model was used to screen a database of 78 compounds and the four highest-scoring compounds and a negative control were tested. Among them, compound (73) (Fig. (13)) was the most potent derivative, satisfying all the features of the pharmacophore model [ 46].…”

“…(13)) was the most potent derivative, satisfying all the features of the pharmacophore model [ 46]. A molecular docking analysis of compound (73) with STAT1 and STAT5 demonstrated that this compound is able to bind to both of them with unfavorable binding scores. A STAT3 DNA-binding assay was performed to examine the effect of the hit compound on DNA-binding activity, treating nuclear extracts from EGF-stimulated cells with the new compound and S3I-201 (74) (a known STAT3 inhibitor, Fig.…”

“…Although tanshinone IIA ( 27) was described as a pro-apoptotic agent on human hepatocellular carcinoma cells [ 69,70], human promyelocytic leukemic cells [ 62], human colon adenocarcinoma cells [ 71] and human erythroleukemic cells, it is better-known for its antiinflammatory properties [ 62,72]. In HCT-116 colon cancer cells, cryptotanshinone inhibited STAT3 activity in a dose-dependent way (IC50 = 4.6 μM) [ 73], while tanshinone IIA showed no inhibitory activity. Cryptotanshinone was later tested on DU145 prostate cancer cell line, displaying substantial growth inhibitory effect [ 62].…”

Targeting Lineage-Specific Transcription Factors and Cytokines of the Th17/Treg Axis by Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone Attenuates TNBS-Induced Experimental Colitis

“…We have also shown that these novel pyrrolo[3,4- d ]pyridazinone derivatives can alleviate inflammatory response in the carrageenan-evoked inflammation model and their mechanism of action might be related to the decrease in the PGE 2 , TNF-α, and MPO levels and the reduction in inflammatory cell infiltration in inflamed tissues [ 20 ]. Several other studies have indicated that compounds based on both pyridazinone [ 21 ] and 1,3,4-oxadiazole [ 22 , 23 , 24 ] scaffolds are able to interfere with the STAT3 pathway, which is involved in Th17 cells differentiation [ 8 ].…”

Pharmacokinetic evaluation, molecular docking and in vitro biological evaluation of 1, 3, 4-oxadiazole derivatives as potent antioxidants and STAT3 inhibitors

“…The 1, 3, 4-oxadiazole scaffold is extensively used in the inhibition of STAT3 in various cancer cells. Dell'Orto et al [22] showed that an oxadiazole based compound effectively inhibited the activation of STAT3 by targeting the STAT3-SH2 domain in a dose-dependent manner. Shin et al [23] reported that oxadiazoles containing ureido derivatives inhibited STAT3 signaling by blocking the upstream tyrosine kinases involved in the activation of STAT3.…”