N-Sulfonyl-aminobiaryls as Antitubulin Agents and Inhibitors of Signal Transducers and Activators of Transcription 3 (STAT3) Signaling

Abstract

A series of N-sulfonyl-aminobiaryl derivatives have been examined as novel antitubulin agents. Compound 21 [N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide] exhibits remarkable antiproliferative activity against four cancer cell lines (pancreatic AsPC-1, lung A549, liver Hep3B, and prostate PC-3) with a mean GI50 value of 57.5 nM. Additional assays reveal that 21 inhibits not only tubulin polymerization but also the phosphorylation of STAT3 inhibition with an IC50 value of 0.2 μM. Four additional compounds (8, 10, 19, and 35) are also able to inhibit this phosphorylation. This study describes novel N-sulfonyl-aminobiaryl (biaryl-benzenesulfonamides) as potent anticancer agents targeting both STAT3 and tubulin.

MPT0G066, a novel anti-mitotic drug, induces JNK-independent mitotic arrest, JNK-mediated apoptosis and potentiates antineoplastic effect of cisplatin in ovarian cancer

“…1B ). Compared with our previous finding, MPT0G066 exert its antiproliferative effect most efficaciously in ovarian cancer cells 11 . Further, MTT assay showed that MPT0G066 repressed SKOV3 and A2780 cell viability with an IC 50 value of 0.44 μM and 0.45 μM respectively ( Fig.…”

LTP-1, a novel antimitotic agent and Stat3 inhibitor, inhibits human pancreatic carcinomas in vitro and in vivo

“…Previously, we have screened growth inhibition activities of arylsulfonamide compounds designed as Stat3 inhibitors against pancreatic cancer cell lines 12 , as Stat3 activation is important for cancer progression 3 . According to the results of cell growth inhibition activities by using the SRB assay, LTP-1 showed most effective growth inhibition activity with GI 50 values of 0.23 ± 0.01 and 0.42 ± 0.16 μM in AsPC-1 and PANC-1 cells, respectively ( Fig.…”

“…2A using a cell-free tubulin polymerization assay. Since Stat3 and tubulin have been reported that physically associate with each other 18 19 , LTP-1, which was previously designed as a Stat3 inhibitor 12 , may cause tubulin depolymerization partly due to Stat3 inhibition effect in cell level and lead to potentiate the LTP-1-induced mitotic arrest to reach plateau phase that no dose-dependent effect could be seen under LTP-1 treatment ( Fig. 3C ).…”

“…Here, we reported that LTP-1, a novel arylsulfonamide, exhibited tubulin binding ability to induce mitotic arrest in pancreatic cancer cell, and polyploidy followed by apoptosis after long-term treatment. Furthermore, LTP-1, which was first designed as a Stat 3 inhibitor 12 , inhibited Stat 3 phosphorylation and inhibited tumor growth significantly in a pancreatic xenograft model in vivo . These results suggest that LTP-1 could be a therapeutic option for pancreatic cancer treatment.…”

“…Although there is abundant evidence supporting the role of Stat3 in pancreatic cancer to justify the discovery of novel Stat3 therapeutics, only few show promising activity in terms of Stat3 inhibition in vitro and an associated antitumor effect 3 . LTP-1 was selected from a series of arylsulfonamide compounds, which was designed as an Stat3 targeting inhibitor previously 12 . In this study, we found that LTP-1 inhibited pancreatic cancer cell growth and caused mitotic arrest, by directly binding to tubulin and acted like a tubulin destabilizing agent.…”