Antitumor activity of a novel oral signal transducer and activator of transcription 3 inhibitor YHO‐1701

Abstract

The signal transducer and activator of transcription 3 (STAT3) signaling pathway is a key mediator of cancer cell proliferation, survival and invasion. Aberrant STAT3 has been demonstrated in various malignant cancers. YHO-1701 is a novel quinolinecarboxamide derivative generated from STX-0119. Here, we examined the effect of YHO-1701 on STAT3 and evaluated antitumor activity of YHO-1701 as a single agent and in combination. YHO-1701 inhibited STAT3-SH2 binding to phospho-Tyr peptide selectively and more potently than STX-0119 in biochemical assays. Molecular docking studies with STAT3 suggested more stable interaction of YHO-1701 with the SH2 domain. YHO-1701 exhibited approximately 10-fold stronger activity than STX-0119 in abrogating the STAT3 signaling pathway of human oral cancer cell line SAS. YHO-1701 also blocked multi-step events by inhibiting STAT3 dimerization and suppressed STAT3 promoter activity. As expected, YHO-1701 exerted strong antiproliferative activity against human cancer cell lines addicted to STAT3 signaling. Orally administered YHO-1701 showed statistically significant antitumor effects with long exposure to high levels of YHO-1701 at tumor sites in SAS xenograft models. Moreover, combination regimen with sorafenib led to significantly stronger antitumor activity.In addition, the suppression level of survivin (a downstream target) was superior for the combination as compared with monotherapy groups within tumor tissues. Thus, YHO-1701 had a favorable specificity for STAT3 and pharmacokinetics after oral treatment; it also contributed to the enhanced antitumor activity of sorafenib. The evidence presented here provides justification using for this approach in future clinical settings. K E Y W O R D Scombination therapy, SH2 domain, signaling pathway, sorafenib, STAT3 inhibitor | 1775 NISHISAKA et Al.

Efficacy of combination treatment using YHO-1701, an orally active STAT3 inhibitor, with molecular-targeted agents on cancer cell lines

“…3B, 4B, and 5B). Furthermore, YHO-1701 downregulated p-STAT3 expression in all cancer cell lines, consistent with the previous observation that YHO-1701 also inactivated the STAT3 signaling pathway in SAS cells 8 .…”

“…5B). The survivin level was believed to be offset, since YHO-1701 was also capable of suppressing survivin, consistent with our previous observation where it was abrogated through inhibiting STAT3 dimerization and/or STAT3 phosphorylation 8 . In contrast to the moderate suppressions by singledrug treatments, the combination treatments strongly inhibited survivin levels in all sets (Figs.…”

“…Interestingly, the YHO-1701/sorafenib combination exhibited an antiproliferative synergistic effect in SAS oral cancer cells as noted elsewhere 8 . This combination and the combination with another multikinase inhibitor, vandetanib, also displayed synergistic inhibitory effects on the growth of both thyroid cancer cell lines.…”

“…Regarding survivin, some studies have shown its potential characteristics as a useful biomarker 35,36 . We believe that a series of experimental results, including our previous data, could render survivin a promising marker in YHO-1701 treatment 8 . Our study has demonstrated additive or synergistic effects in two-thirds of the "combination + model" sets; however, the underlying mechanisms responsible for the combination effect remain to be completely elucidated.…”

“…The plasma YHO-1701 concentrations were determined with LC-MS/MS as described previously 8 . Brie y, non-tumor-bearing mice were orally administered either single (n = 3) or 5-day repeated (n = 6) doses of YHO-1701 at 80 mg/kg, and the values of C max were calculated using the mean values.…”