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Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction.

ABSTRACT: Small molecule inhibitor of the bromodomain and extraterminal domain (BET) family proteins is a promising option for cancer treatment. However, current BET inhibitors are limited by their potency or oral bioavailability. Here we report the discovery and characterization of NHWD-870, a BET inhibitor that is more potent than three major clinical stage BET inhibitors BMS-986158, OTX-015, and GSK-525762. NHWD-870 causes tumor shrinkage or significantly suppresses tumor growth in nine xenograft or syngeneic models. In addition to its ability to downregulate c-MYC and directly inhibit tumor cell proliferation, NHWD-870 blocks the proliferation of tumor associated macrophages (TAMs) through multiple mechanisms, partly by reducing the expression and secretion of macrophage colony-stimulating factor CSF1 by tumor cells. NHWD-870 inhibits CSF1 expression through suppressing BRD4 and its target HIF1α. Taken together, these results reveal a mechanism by which BRD4 inhibition suppresses tumor growth, and support further development of NHWD-870 to treat solid tumors.

SUBMITTER: Yin M

PROVIDER: S-EPMC7156724 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveMetastasis causes approximately 90% of cancer-related deaths, including in cervical cancer patients. Uncontrolled cell proliferation, migration, and cancer stemness act as critical events in primary tumor growth and cancer metastasis progression in cervical cancer. Here, we investigated the anti-proliferative, anti-migration, and cancer stemness inhibition activity of N-phenyl pyrazoline derivatives against cervical cancer cells.MethodsThe chalcone and phenylhydrazine were used to synthesize the N-phenyl pyrazoline 2/5 (P2 and P5). The MTT, colony formation, and wound healing assays were performed to evaluate the N-phenyl pyrazoline effect in HeLa cells. The N-phenyl pyrazoline's protein target was predicted using SwissTargetPrediction and AutoDock Vina software. The Western blotting assay was performed to evaluate the target proteins. The public dataset analysis was used to confirm the clinical relevance of target protein in cervical cancer patients.ResultsN-phenyl pyrazoline 2 and 5 were successfully synthesized. The N-phenyl pyrazolines 2 and 5 exhibit cytotoxic effect in HeLa cell line with 20.26 µM, 4.708 µM of IC50, respectively. Further study shows that the N-phenyl pyrazoline 5 suppresses the cell proliferation and migration ability of HeLa cell line in a dose-dependent manner. Target prediction and molecular docking reveal that EGFR and ERBB2 protein as the main target of the N-phenyl pyrazoline 5 compound. The N-phenyl pyrazoline 5 suppresses the EGFR expression level but not the total ERK1/2. Public data and GSEA analysis found that the EGFR high expression level is positively associated with poor survival, cancer metastasis-related signaling pathways, and cancer stem cell markers in cervical cancer patients. In addition, the N-phenyl pyrazoline 5 reduces the HeLa's tumorsphere size and cancer stem cell marker, CD133.ConclusionN-phenyl pyrazoline 5 suppresses the cell viability, proliferation, migration, and cancer stem cell-like phenotype of cervical cancer cells via EGFR inhibition.

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Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction.

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