Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung Cancer

Abstract

Lung cancer is the leading type of malignancy in terms of occurrence and mortality in the global context. STAT3 is an oncogenic transcription factor that is persistently activated in many types of human malignancies, including lung cancer. In the present report, new oxadiazole conjugated indazoles were synthesized and examined for their anticancer potential in a panel of cancer cell lines. Among the new compounds, 2-(3-(6-chloro-5-methylpyridin-3-yl)phenyl)-5-(1-methyl-1H-indazol-3-yl)-1,3,4-oxadiazole (CHK9) showed consistently good cytotoxicity towards lung cancer cells with IC50 values ranging between 4.8–5.1 µM. The proapoptotic effect of CHK9 was further demonstrated by Annexin-FITC staining and TUNEL assay. In addition, the effect of CHK9 on the activation of STAT3 in lung cancer cells was examined. CHK9 reduced the phosphorylation of STAT3Y705 in a dose-dependent manner. CHK9 had no effect on the activation and expression of JAK2 and STAT5. It also reduced the STAT3-dependent luciferase reporter gene expression. CHK9 increased the expression of proapoptotic (p53 and Bax) proteins and decreased the expression of the antiapoptotic (Bcl-2, Bcl-xL, BID, and ICAM-1) proteins. CHK9 displayed a significant reduction in the number of tumor nodules in the in vivo lung cancer model with suppression of STAT3 activation in tumor tissues. CHK9 did not show substantial toxicity in the normal murine model. Overall, CHK9 inhibits the growth of lung cancer cells and tumors by interfering with the STAT3 signaling pathway.

Synthesis and Anticancer Evaluation of New 1,3,4-Oxadiazole Derivatives

“…The predictive studies using the PASS application indicated the inhibition of the STAT3 transcription factor as the most probable anticancer mechanism. Recent evidence shows that the 1,3,4-oxadiazole scaffold is frequently used in the structure of STAT3 inhibitors active against various cancer cells [ 39 , 40 , 41 ]. STAT3 is closely related to the occurrence of cancers and is an attractive therapeutic target for oncology and drug development.…”

Anticancer Activities of Some Heterocyclic Compounds Containing an Oxygen Atom: A Review

“…The anticancer potential of a new oxadiazole conjugated with an indazole that Malojirao and colleagues had produced was tested using several cancer cell lines. Among the novel substances, compound IXX always demonstrated the highest anticancer effect against cancer cells in the lung, with IC50 values ranging between 4.8-5.1 µM [30].…”

Design and Activity of Novel Oxadiazole Based Compounds That Target Poly(ADP-ribose) Polymerase

“…G007-LK was co-crystallized with the PARP catalytic domain of TNKS2 and bound to the extended adenosine binding pocket of PARP, indicative of unique oxadiazole binding to PARP catalytic domains [ 20 ]. Recently, compound 2 ( Figure 1 ) was also reported to inhibit the autophagy activating kinase 1 (ULK1) with an IC 50 of 14 nM, and ULK1/2 inhibition in combination with Olaparib [ 21 ]. In continuation of the effort in the synthesis of novel oxadiazoles [ 22 , 23 , 24 , 25 , 26 , 27 , 28 ], herein synthesis of oxadiazoles with substitutions of pyridine, biphenyl, pyrimidine, and thiophene rings that target PARP1 and the efficacy of these compounds in BRCA wild-type estrogen receptor positive (ER+) and triple-negative breast cancer (TNBC) cells is reported.…”