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A novel series of aminotrimethylpyridinol and aminodimethylpyrimidinol derivatives were designed and synthesised for FGFR4 inhibitors. Structure-activity relationship on the FGFR4 inhibitory activity of the new compounds was clearly elucidated by an intensive molecular docking study. Anti-cancer activity of the compounds was evaluated using hepatocellular carcinoma (HCC) cell lines and a chick chorioallantoic membrane (CAM) tumour model. Compound 6O showed FGFR4 inhibitory activity over FGFR1 - 3. Compared to the positive control BLU9931, compound 6O exhibited at least 8 times higher FGFR4 selectivity. Strong anti-proliferative activity of compound 6O was observed against Hep3B, an HCC cell line which was a much more sensitive cell line to BLU9931. In vivo anti-tumour activity of compound 6O against Hep3B-xenografted CAM tumour model was almost similar to BLU9931. Overall, compound 6O , a novel derivative of aminodimethylpyrimidinol, was a selective FGFR4 kinase inhibitor blocking HCC tumour growth.

Sorafenib is recommended as the primary therapeutic drug for patients with hepatocellular carcinoma. To discover a new compound that avoids low response rates and toxic side effects that occur in sorafenib therapy, we designed and synthesized new hybrid compounds of sorafenib and 2,4,5-trimethylpyridin-3-ols. Compound 6 was selected as the best of 24 hybrids that inhibit each of the four Raf kinases. The anti-proliferative activity of 6 in HepG2, Hep3B, and Huh7 cell lines was slightly lower than that of sorafenib. However, in H6c7 and CCD841 normal epithelial cell lines, the cytotoxicity of 6 was much lower than that of sorafenib. In addition, similar to sorafenib, compound 6 inhibited spheroid forming ability of Hep3B cells in vitro and tumour growth in a xenograft tumour model of the chick chorioallantoic membrane implanted with Huh7 cells. Compound 6 may be a promising candidate targeting hepatocellular carcinoma with low toxic side effects on normal cells.

Chemotherapy for cholangiocarcinoma (CCA) is not quite successful. In this study, we revisited the possibility of artesunate (ART) and chloroquine (CQ), the antimalarial drugs, as therapeutic agents against CCA. The possible mechanisms of these drugs to exert cytotoxicity on CCA cells were also explored. The effects of ART and CQ on proliferation and death patterns of two CCA cell lines, KKU-214 and its highly metastatic subtype KKU-214L5, were examined using water soluble tetrazolium (WST) assay and time-lapse photometry, respectively. To differentiate and verify the death patterns between necrosis and apoptosis, lactate dehydrogenase (LDH) release, and caspase 3 activity were measured. CellROXTM green reagent staining method was used to assess reactive oxygen species (ROS) production in ART- and CQ-treated cells. ART and CQ significantly inhibited proliferation of CCA cells. Both drugs kill malarial parasites via similar mechanism depending on ROS formation, however, ART induced necrotic cell death and CQ induced apoptotic cell death in CCA cells. ART induced LDH release, whereas CQ activated caspase 3, confirming induction of necrotic and apoptotic cell deaths by ART and CQ, respectively. ART treatment induced higher ROS production than CQ. ART and CQ induce CCA cells death via different death pathways. ART should be suitable for necrosis-sensitive CCA, whereas CQ is more suitable for apoptosis-sensitive CCA.

Macrophage colony-stimulating factor (M-CSF, also known as CSF1) in tumor tissues stimulates tumor growth and tumor-induced angiogenesis through an autocrine and paracrine action on CSF1 receptor (CSF1R). In the present study, novel bioisosteres of pexidartinib (1) were synthesized and evaluated their inhibitory activities against CSF1R kinase and tumor growth. Among newly synthesized bioisosteres, compound 3 showed the highest inhibition (95.1%) against CSF1R tyrosine kinase at a fixed concentration (1 μM). The half maximal inhibitory concentration (IC 50) of pexidartinib (1) and compound 3 was 2.7 and 57.8 nM, respectively. Unlike pexidartinib (1), which cross-reacts to three targets with structural homology, such as CSF1R, c-KIT, and FLT3, compound 3 inhibited CSF1R, c-KIT, but not FLT3, indicating compound 3 may be a more selective CSF1R inhibitor than pexidartinib (1). The inhibitory effect of compound 3 on the proliferation of various cancer cell lines was the strongest in U937 cells followed by THP-1 cells. In the case of cancer cell lines derived from solid tumors, the anti-proliferative activity of compound 3 was weaker than pexidartinib (1), except for Hep3B. However, compound 3 was safer than pexidartinib (1) in terminally differentiated normal cells such as macrophages. Pexidartinib (1) and compound 3 suppressed the production of CSF1 in Hep3B liver cancer cells as well as in the co-culture of Hep3B cells and macrophages. Also, pexidartinib (1) and compound 3 decreased the population ratio of the M2/M1 phenotype and inhibited their migration. Importantly, compound 3 preferentially inhibited M2 phenotype over M1, and the effect was about 4 times greater than that of pexidartinib (1). In addition, compound 3 inhibited maintenance of cancer stem cell population. In a chick chorioallantoic membrane (CAM) tumor model implanted with Hep3B cells, tumor growth and tumor-induced angiogenesis were significantly blocked by compound 3 to a similar extent as pexidartinib (1). Overall, compound 3 , a bioisostere of pexidartinib, is an effective dual inhibitor to block CSF1R kinase and CSF1 production, resulting in significant inhibition of tumor growth. [Display omitted] • Compound 3 , a novel bioisostere of pexidartinib, inhibited CSF1R kinase. • Antiproliferative activity of compound 3 has more selectivity against leukemia cell lines. • Compound 3 inhibited CSF1 secretion from Hep3B hepatocellular carcinoma cells. • Compound 3 inhibited the population ratio of macrophage M2 over M1 phenotype and their migration ability. • Compound 3 inhibited tumor growth and angiogenesis in CAM tumor model implanted with Hep3B cells. [ABSTRACT FROM AUTHOR]