Within the context of a new tumor-targeting strategy termed "combi-targeting," we designed RB24 to inhibit epidermal growth factor receptor (EGFR) or Her2 phosphorylation and to further degrade upon hydrolysis to 4-(3'-bromophenylamino)-6-aminoquinazoline (RB10; another EGFR/Her2 inhibitor) plus a strong DNA-alkylating species. 6-(3-Acetoxymethyl-3-methyltriazenyl)-4-(3'-bromophenylamino)quinazoline (RB24) showed significant antiproliferative activity against human breast cancer cells, and transfection of one such cell line, MDA-MB-435, with ErbB1 or ErbB2 (Her2) dramatically enhanced cell death by apoptosis. RB24 was capable of releasing 2- to 3-fold higher levels of RB10 in the transfectants than in their wild-type counterparts. More importantly, RB10 was abundantly distributed in the perinuclear region of the cells, and its elevated levels in the ErbB transfectants were concomitant with increased levels of DNA lesions in the latter cells. This selectivity could be abolished by coincubation of the cells with exogenous RB10, suggesting that the entire combi-molecule may bind primarily to its cognate perinuclear sites before degradation. This localization may exert a bystander effect, allowing the alkylating species to be abundantly propagated into the nucleus. Cell response to this novel targeting mechanism was mediated by 1) activation of c-Jun NH(2)-terminal kinase in response to DNA damage and 2) down-regulation of Bad through blockade of EGFR tyrosine kinase activity: two events that cooperatively converged into enhancement of apoptosis in the oncogene-transfected cells.
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http://dx.doi.org/10.1124/jpet.109.160085 | DOI Listing |
J Med Chem
January 2025
Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China.
Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether and biaryl as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CL compounds while maintaining a WT selectivity margin.
View Article and Find Full Text PDFPLoS Pathog
January 2025
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
The intracellular protozoan Toxoplasma gondii manipulates host cell signaling to avoid targeting by autophagosomes and lysosomal degradation. Epidermal Growth Factor Receptor (EGFR) is a mediator of this survival strategy. However, EGFR expression is limited in the brain and retina, organs affected in toxoplasmosis.
View Article and Find Full Text PDFBiomol Biomed
January 2025
Necmettin Erbakan University, Meram Faculty of Medicine, Department of Medical Oncology, Konya, Turkey.
The cysteine-rich epidermal growth factor ligand domain 2 protein (CRELD2) is associated with pathways that regulate epithelial-to-mesenchymal transition, a critical process driving cancer metastasis. This study aimed to determine the prognostic value of CRELD2 status on survival outcomes in triple-negative breast cancer (TNBC). Seventy patients were included in the study.
View Article and Find Full Text PDFAnticancer Drugs
January 2025
Department of General Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center.
In gastric cancer, the relationship between human epidermal growth factor receptor 2 (HER2), the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway, and autophagy remains unclear. This study examines whether HER2 regulates autophagy in gastric cancer cells via the cGAS-STING signaling pathway, influencing key processes such as cell proliferation and migration. Understanding this relationship could uncover new molecular targets for diagnosis and treatment.
View Article and Find Full Text PDFTissue Eng Part C Methods
January 2025
CiRA Foundation, Research and Development Center, Osaka, Japan.
Mouse embryonic fibroblasts (MEFs) have been widely used as feeder cells in embryonic stem cell cultures because they can mimic the embryonic microenvironment. Milk fat globule-epidermal growth factor 8 (MFGE8) is expressed during mouse gonadal development, 10.5-13.
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