2,4,5-Trichloro-6-((2,4,6-trichlorophenyl)amino)isophthalonitrile, Exerts Anti-bladder Activities through IGF-1R/STAT3 Signaling.

2,4,5-Trichloro-6-((2,4,6-trichlorophenyl)amino)isophthalonitrile (SYD007) is a small molecule compound that was synthesized according to the structure of diarylamine. In this study, we evaluated the anti-bladder activities of SYD007, and determined its cytotoxic mechanism. We found that SYD007 exerted cytotoxicity to bladder cancer cells. Furthermore, SYD007 induced bladder cancer cell early apoptosis and arrested cell cycle. Mechanistically, SYD007 suppressed phosphorylated signal transducer and activator of transcription 3 (p-STAT3) (Tyr705) level in parallel with increases of p-extracellular signal-regulated kinase (ERK) and p-AKT. SYD007 significantly inhibited insulin-like growth factor 1 (IGF-1)-induced STAT3 activation through down-regulation of total IGF-1R level. No dramatic changes in IGF-1R mRNA levels were observed in SYD007-treated cells, suggesting that SYD007 acted primarily at a posttranscriptional level. Using molecular docking analysis, SYD007 was identified as an IGF-1R inhibitor. In summary, we reported that SYD007 exerted anti-bladder activities, and these effects were partially due to inhibition of IGF-1R/STAT3 signaling.

Design, Synthesis and Structure-Activity Relationships of Novel Diaryl Urea Derivatives as Potential EGFR Inhibitors.

Two novel series of diaryl urea derivatives 5a-i and 13a-l were synthesized and evaluated for their cytotoxicity against H-460, HT-29, A549, and MDA-MB-231 cancer cell lines in vitro. Therein, 4-aminoquinazolinyl-diaryl urea derivatives 5a-i demonstrated significant activity, and seven of them are more active than sorafenib, with IC50 values ranging from 0.089 to 5.46 µM. Especially, compound 5a exhibited the most active potency both in cellular (IC50 = 0.15, 0.089, 0.36, and 0.75 µM, respectively) and enzymatic assay (IC50 = 56 nM against EGFR), representing a promising lead for further optimization.

Design, synthesis and biological evaluation of novel 4-arylaminopyrimidine derivatives possessing a hydrazone moiety as dual inhibitors of L1196M ALK and ROS1.

A series of 4-arylaminopyrimidine derivatives possessing a hydrazone moiety were designed, synthesized and evaluated for their biological activity. Most compounds exhibited moderate to excellent cytotoxic activity against ALK-addicted KARPAS299 and ROS1-addicted HCC78, while also showing much less potent activity against A549, H460 and HT-29, whose growth were not dependent on ALK and/or ROS1, as compared with crizotinib and ceritinib. The most promising compound, 7b, showed high antiproliferative effects on ALK-addicted KARPAS299 and ROS1-addicted HCC78 cell lines with IC50 of 20 nM and 28 nM, respectively, but showed no inhibitory activity against A549, H460 and HT-29. The enzymatic assay identified 7b as a potent and selective ALK and ROS1 dual inhibitor with IC50 of 2.5 nM and 2.7 nM, respectively. It also exhibited good inhibitory activity against the L1196M ALK with an IC50 value of 67 nM.

Design and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives bearing an imidazolone moiety as c-Met kinase inhibitors.

A series of 4-(2-fluorophenoxy)quinoline derivatives containing an imidazolone moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, H460, HT-29 and MKN-45). Most compounds showed moderate to excellent activities in enzyme and cellular assays. The most promising analog, 58 (c-Met IC50=1.42 nM), displayed 2.1-, 8.6-fold increase against H460, and MKN-45 cell lines, respectively, compared with foretinib. An analysis of structure-activity relationships revealed that an ortho substituted phenyl ring as well as an N-unsubstituted imidazolone linker is favorable for antitumor activity.