The extracellular matrix (ECM) has been demonstrated to be dysregulated and crucial for malignant progression in gastric cancer (GC), but the mechanism is not well understood. Here, that discoidin domain receptor 1 (DDR1), a principal ECM receptor, is recognized as a key driver of GC progression is reported. Mechanistically, DDR1 directly interacts with the PAS domain of hypoxia-inducible factor-1α (HIF-1α), suppresses its ubiquitination and subsequently strengthens its transcriptional regulation of angiogenesis. Additionally, DDR1 upregulation in GC cells promotes actin cytoskeleton reorganization by activating HIF-1α/ Ras Homolog Family Member A (RhoA)/Rho-associated protein kinase 1 (ROCK1) signaling, which in turn enhances the metastatic capacity. Pharmacological inhibition of DDR1 suppresses GC progression and angiogenesis in patient-derived xenograft (PDX) and organoid models. Taken together, this work first indicates the effects of the DDR1-HIF-1α axis on GC progression and reveals the related mechanisms, providing experimental evidence for DDR1 as a therapeutic target for GC.

OBJECTIVE: This study investigated the involvement of discoidin domain receptor (DDR) in dry eye and assessed the potential of specific DDR inhibitors as a therapeutic strategy for dry eye by exploring the underlying mechanism.
METHODS: Dry eye was induced in Wistar rats by applying 0.2% benzalkonium chloride (BAC), after which rats were treated topically for 7 days with DDR1-IN-1, a selective inhibitor of DDR1. Clinical manifestations of dry eye were assessed on Day-7 post-treatment. Histological evaluation of corneal damage was performed using haematoxylin and eosin (H&E) staining. In vitro, immortalized human corneal epithelial cells (HCECs) exposed to hyperosmotic stress (HS) were treated with varying doses of DDR1-IN-1 for 24 h. The levels of lipid peroxidation in dry eye corneas or HS-stimulated HCECs were assessed. Protein levels of DDR1/DDR2 and related pathways were detected by western blotting. The cellular distribution of acyl-CoA synthetase long chain family member 4 (ACSL4) and Yes-associated protein (YAP) was evaluated using immunohistochemistry or immunofluorescent staining.
RESULTS: In dry eye corneas, only DDR1 expression was significantly up-regulated compared with normal controls. DDR1-IN-1 treatment significantly alleviated dry eye symptoms in vivo. The treatment remarkably reduced lipid hydroperoxide (LPO) levels and suppressed the expression of ferroptosis markers, particularly ACSL4. Overexpression or reactivation of YAP diminished the protective effects of DDR1-IN-1, indicating the involvement of the Hippo/YAP pathway in DDR1-targeted therapeutic effects.
CONCLUSIONS: This study confirms the significance of DDR1 in dry eye and highlights the potential of selective DDR1 inhibitor(s) for dry eye treatment.

This study aimed to develop the first dual-target small molecule inhibitor concurrently targeting Discoidin domain receptor 1 (DDR1) and Epidermal growth factor receptor (EGFR), which play a crucial interdependent roles in non-small cell lung cancer (NSCLC), demonstrating a synergistic inhibitory effect. A series of innovative dual-target inhibitors for DDR1 and EGFR were discovered. These compounds were designed and synthesized using structural optimization strategies based on the lead compound BZF02, employing 4,6-pyrimidine diamine as the core scaffold, followed by an investigation of their biological activities. Among these compounds, D06 was selected and showed micromolar enzymatic potencies against DDR1 and EGFR. Subsequently, compound D06 was observed to inhibit NSCLC cell proliferation and invasion. Demonstrating acceptable pharmacokinetic performance, compound D06 exhibited its anti-tumor activity in NSCLC PC-9/GR xenograft models without apparent toxicity or significant weight loss. These collective results showcase the successful synthesis of a potent dual-targeted inhibitor, suggesting the potential therapeutic efficacy of co-targeting DDR1 and EGFR for DDR1/EGFR-positive NSCLC.

Discoidin domain receptor (DDR)-1 has a crucial role in regulating vital processes, including cell differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. Overexpression or activation of DDR1 in various pathological scenarios makes it a potential therapeutic target for the treatment of cancer, fibrosis, atherosclerosis, and neuropsychiatric, psychiatric, and neurodegenerative disorders. In this review, we summarize current therapeutic approaches targeting DDR1 from a medicinal chemistry perspective. Furthermore, we analyze factors other than issues of low selectivity and risk of resistance, contributing to the infrequent success of DDR1 inhibitors. The complex interplay between DDR1 and the extracellular matrix (ECM) necessitates additional validation, given that DDR1 might exhibit complex and synergistic interactions with other signaling molecules during ECM regulation. The mechanisms involved in DDR1 regulation in cancer and inflammation-related diseases also remain unknown.

Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase (RTK) and plays pivotal roles in regulating cellular functions such as proliferation, differentiation, invasion, migration, and matrix remodeling. DDR1 is involved in the occurrence and progression of many human diseases, including cancer, fibrosis, and inflammation. Therefore, DDR1 represents a highly promising therapeutic target. Although no selective small-molecule inhibitors have reached clinical trials to date, many molecules have shown therapeutic effects in preclinical studies. For example, BK40143 has demonstrated significant promise in the therapy of neurodegenerative diseases. In this context, our perspective aims to provide an in-depth exploration of DDR1, encompassing its structure characteristics, biological functions, and disease relevance. Furthermore, we emphasize the importance of understanding the structure-activity relationship of DDR1 inhibitors and highlight the unique advantages of dual-target or multitarget inhibitors. We anticipate offering valuable insights into the development of more efficacious DDR1-targeted drugs.

Glioblastomas (GBM) are the most common primary brain tumors in adults and associated with poor clinical outcomes due to therapy resistances and destructive growth. Interactions of cancer cells with the extracellular matrix (ECM) play a pivotal role in therapy resistances and tumor progression. In this study, we investigate the functional dependencies between the discoidin domain receptor 1 (DDR1) and the integrin family of cell adhesion molecules for the radioresponse of human glioblastoma cells. By means of an RNA interference screen on DDR1 and all known integrin subunits, we identified co-targeting of DDR1/integrin β3 to most efficiently reduce clonogenicity, enhance cellular radiosensitivity and diminish repair of DNA double strand breaks (DSB). Simultaneous pharmacological inhibition of DDR1 with DDR1-IN-1 and of integrins αVβ3/αVβ5 with cilengitide resulted in confirmatory data in a panel of 2D grown glioblastoma cultures and 3D gliospheres. Mechanistically, we found that key DNA repair proteins ATM and DNA-PK are altered upon DDR1/integrin αVβ3/integrin αVβ5 inhibition, suggesting a link to DNA repair mechanisms. In sum, the radioresistance of human glioblastoma cells can effectively be declined by co-deactivation of DDR1, integrin αVβ3 and integrin αVβ5.

The tyrosine kinase family receptor of discoidin domain receptors (DDR1 and DDR2) is known to be activated by extracellular matrix collagen catalytic binding protein receptors. They play a remarkable role in cell proliferation, differentiation, migration, and cell survival. DDR1 of the DDR family regulates matrix-metalloproteinase, which causes extracellular matrix (ECM) remodeling and reconstruction during unbalanced homeostasis. Collagenous-rich DDR1 triggers the ECM of cartilage to regenerate the cartilage tissue in osteoarthritis (OA) and temporomandibular disorder (TMD). Moreover, DDR2 is prominently present in the fibroblasts, smooth muscle cells, myofibroblasts, and chondrocytes. It is crucial in generating and breaking collagen vital cellular activities like proliferation, differentiation, and adhesion mechanisms. However, the deficiency of DDR1 rather than DDR2 was detrimental in cases of OA and TMDs. DDR1 stimulated the ECM cartilage and improved bone regeneration. Based on the above information, we made an effort to outline the advancement of the utmost promising DDR1 and DDR2 regulation in bone and cartilage, also summarizing their structural, biological activity, and selectivity.

Transmembrane 4 L6 family member 1 (TM4SF1) and discoidin domain receptor 1 (DDR1) are expressed in numerous types of cancer, but their expression in epithelial ovarian cancer and the association between their expression and patient prognosis are unclear. The present study aimed to explore the expression of TM4SF1 and DDR1 and their relationship with prognosis in epithelial ovarian cancer. Firstly, the Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA) platforms were used to compare the expression levels of TM4SF1 and DDR1 in ovarian cancer and normal ovarian tissue, and Kaplan-Meier plotter was used to analyze the association between gene expression and patient prognosis. The proteins interacting with TM4SF1 and DDR1 were analyzed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and enrichment analysis of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways was conducted for the interacting proteins. Furthermore, immunohistochemical staining was performed to detect the expression of TM4SF1 and DDR1 protein in epithelial ovarian cancer tissue and to analyze the association between expression and prognosis. The Oncomine and GEPIA analyses showed that the expression levels of TM4SF1 and DDR1 were significantly higher in epithelial ovarian cancer than in normal ovarian tissue, and the analysis of clinical samples revealed that TM4SF1 and DDR1 were coexpressed in some cases. STRING analysis indicated that the TM4SF1 and DDR1 proteins interact with each other. The overall survival and progression-free survival of patients whose epithelial ovarian cancer coexpressed TM4SF1 and DDR1 were significantly shorter than those of patients lacking TM4SF1 and DDR1 coexpression. Multivariate analysis indicated that TM4SF1 and DDR1 protein coexpression was an independent prognostic factor. In summary, TM4SF1 and DDR1 proteins were coexpressed in some epithelial ovarian cancer tissues and appear to be adverse prognostic factors for epithelial ovarian cancer. In addition, TM4SF1 and DDR1 may have an interactive or mutual regulatory mechanism.

In addition to immune cells and fibroblasts, the tumor microenvironment (TME) comprises an extracellular matrix (ECM) which contains collagens (COLs) whose architecture and remodeling dictate cancer development and progression. COL receptors expressed by cancer cells sense signals generated by microenvironmental alterations in COL state to regulate cell behavior and metabolism. Discoidin domain receptor 1 (DDR1) is a key sensor of COL fiber state and composition that controls tumor cell metabolism and growth, response to therapy, and patient survival. This review focuses on DDR1 to NRF2 signaling, its modulation of autophagy and macropinocytosis (MP), and its role in cancer and other diseases. Elucidating the regulation of DDR1 activity and expression under different pathophysiological conditions will facilitate the discovery of new therapeutics.

Euphorbia factor L1 (EFL1), a lathyrane-type diterpenoid from the medicinal herb Euphorbia lathyris L., has been documented to possess various pharmacologic actives. However, the function of EFL1 on breast cancer is not clear. In this study, we explored the effect and mechanism of EFL1 on breast cancer liver metastasis. Female BALB/c mice were subjected to breast cancer-surgical hepatic implantation (SHI) to establish breast cancer liver metastasis model in vivo. At 10 days post-surgery, mice were administrated with EFL1 once daily for a total of 2 weeks. Serum AST and ALT activities, abdominal circumference, peritoneal fluid, tumor weight and volume were determined to assess liver and mesenteric re-metastasis of breast cancer. H&E staining was used to observe morphology changes in tumor, liver and small intestine tissues. ELISA was applied to observe inflammatory levels. Tumor DDR1 expression and immune infiltration were determined using western blotting, immunohistochemistry and flow cytometer methods. Our results showed that EFL1 administration improved liver function (AST and ALT activities), ascites, liver metastasis and mesenteric re-metastasis in SHI mice. Also, SHI-induced inflammatory cell infiltration and IL-1β, IL-6, TNF-α generation in ascites were decreased by EFL1 treatment. Mechanism study revealed that EFL1 intervention enhanced the ratios of CD4+ and CD8+ and CD49b+(NK) T lymphocytes and decreased Treg cells through downregulating DDR1 in the tumor of SHI mice. Furthermore, overexpression of DDR1 abolished the anti-liver metastasis effect and pro-immune infiltration action of EFL1 in SHI mice. Together, our findings suggested that EFL1 protects against breast cancer liver metastasis in vivo by targeting DDR1-mediated immune infiltration.