4-(5-benzo(1-3)dioxol-5-yl-4-pyridin-2-yl-1h-imidazol-2-yl)benzamide and Neoplasms

With the rise of immuno-oncology, small-molecule modulators targeting immune system and inflammatory processes are becoming a research hotspot. This work mainly focuses on key kinases acting as central nodes in immune signaling pathways. Although over thirty small-molecule kinase inhibitors have been approved by FDA for the treatment of various cancers, only a few are associated with immuno-oncology. With the going deep of the research work, more and more immunity protein kinase inhibitors are approved for clinical trials to treat solid tumors and hematologic malignancies by FDA, which remain good prospects. Meanwhile, in-depth understanding of biological function of immunity protein kinases in immune system is pushing the field forward. This article focuses on the development of safe and effective small-molecule immunity protein kinase inhibitors and further work needs to keep the promises of these inhibitors for patients' welfare.

Topics: Humans; Immune System; Immunotherapy; Inflammation; Neoplasms; Protein Kinase Inhibitors

Topics: 3T3 Cells; Animals; Antibiotics, Antineoplastic; Benzamides; Cancer-Associated Fibroblasts; Cell Line, Tumor; Delayed-Action Preparations; Dioxoles; Doxorubicin; Female; Hydrogen-Ion Concentration; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasms; Rotaxanes; Signal Transduction; Transforming Growth Factor beta; Tumor Microenvironment

Epithelial‑mesenchymal transition (EMT) plays an important role in cancer progression, metastasis and drug resistance, and recent studies have revealed that neoplastic epithelial cells regain the stem cell state through EMT. Single‑agent targeted cancer therapy frequently fails due to acquired drug resistance. Therefore, multi‑agent targeted therapy exhibits advantages in fighting cancer cells. In the present study, small molecule inhibitors SB431542 (ALK inhibitor), CHIR99021 (GSK3 pathway inhibitor), PD0325901 (MEK/ERK inhibitor) and valproic acid (VPA; HDAC inhibitor) were applied individually or in combination to HeLa uterine cervix carcinoma cells, 5637 bladder cancer cells and SCC‑15 squamous cell carcinoma cells to clarify their potential effects on cancer cells. Cell morphological alterations, pluripotency and EMT‑related gene expression, cell growth rate, cell migration, signal transduction, cell cycle arrest, CD24‑/CD44+ cell percentage, and in vivo tumor clump formation were evaluated. The results of the present study revealed that VPA treatment induced EMT morphology, upregulated the expression of pluripotency and EMT‑related genes, promoted migration and increased CD24‑/CD44+ cell percentage in all three cell lines. PD0325901, SB431542 and CHIR99021 in combination could significantly inhibit cell growth, suppress expression of pluripotency and EMT‑related genes, curb cell migration, cause cell cycle arrest, decrease CD24‑/CD44+ cell percentage in cell spheres, and delay in vivo cell clump formation of cancer cells. These data indicated that VPA may serve as an EMT and cancer stem cell‑promoting agent that may be useful in establishing a screening system for potential anticancer stem cell drugs. The combined inhibition of MEK/ERK, ALK and GSK3 was revealed to be an effective measure for eliminating cancer stem cells.

Topics: Benzamides; Dioxoles; Diphenylamine; Drug Synergism; Epithelial-Mesenchymal Transition; HeLa Cells; Humans; Neoplasms; Neoplastic Stem Cells; Pyridines; Pyrimidines; Valproic Acid

The transforming growth factor β (TGFβ) stimulates tumor progression and metastasis. Secretion of TGFβ by tumor cells also suppresses an antitumor immune response in which dendritic cells (DCs) play an important role to activate cytotoxic T lymphocytes (CTLs). Herein we report that the small molecule TGFβ signaling inhibitor SB-431542, induces DC maturation in vitro and triggers antitumor activity in vivo. We added SB-431542 to cultures of murine bone-marrow derived DCs (BM-DCs) derived from BALB/c mice and human DCs generated from peripheral monocytes (human DCs) at different concentrations in triplicates and examined expression of co-stimulatory molecules by FACS and production of Interleukin-12 (IL-12) by ELISA. SB induced phenotypic maturation of BM-DCs and human DCs and improved their abilities to produce IL-12 in a dose-dependent manner. SB-431542 also augmented capacity of murine and human DCs to activate naive T cells in allogeneic mixed lymphocyte reaction. Interestingly, SB-431542 augmented the capacity of BM-DCs and human DCs to incorporate FITC-conjugated dextran. Intraperitoneal administration of SB-431542 initiated 3 and 7 days after the implantation of colon-26 cancer cells into the peritoneal cavity of BALB/c mice significantly induced CTL activity against colon-26. We incubated human DCs with SB-431542 and cell lysate of scirrhous gastric cancer cell line OCUM-8, and then examined CTL activities against OCUM-8. CD8 T cells activated by human DCs treated with SB-431542 showed modest augmentation CTL activity against cancer cells. Furthermore, pretreatment of human DCs with SB-431542 upregulated cytotoxic activity against K562 cells, suggesting SB should have potential to activate DCs to natural killer cells. In conclusion, TGFβ receptor I kinase inhibitor such as SB-431542 might induce anti-tumor immune response in immuno-tolerant patients associated with TGFβ activity.

Topics: Animals; Antineoplastic Agents; Benzamides; Cell Differentiation; Cells, Cultured; Combined Modality Therapy; Dendritic Cells; Dioxoles; Female; Humans; Immunotherapy, Active; K562 Cells; Mice; Mice, Inbred BALB C; Neoplasms; Transforming Growth Factor beta; Xenograft Model Antitumor Assays