UNC2025

UNC2025 was effective in both tumour types with superior efficacy over BGB324. Finally, we found that TAMs are expressed by tumour-associated macrophages in meningioma and schwannoma tumours and that UNC2025 strongly depleted macrophages in both tumour types.

Importantly, pharmacological inhibition of either JAK1 by filgotinib or TAM kinases by UNC2025 sensitizes Ewing sarcoma to chemotherapy in vitro and in vivo. Excitingly, the TAM kinase inhibitor MRX-2843 currently in human clinical trials to treat AML and advanced solid tumors, enhances chemotherapy efficacy to further suppress Ewing sarcoma tumor growth in vivo. Our findings reveal an Ewing sarcoma chemoresistance mechanism with an immediate translational value.

Our findings demonstrate the potential value of MerTK as a prognostic biomarker for gastric adenocarcinoma. Targeting MerTK may become a new treatment option, especially for patients with advanced tumors, and may overcome resistance to established chemotherapies.

Furthermore, transcriptional profiles of macrophages indicated robust pro-inflammatory reprogramming (elevated Nos2 and Il12; suppressed Arg1 and Mrc1 expression levels) for a subset of these immuno-stimulatory agents (UNC2025 and R848)...Finally, in an intradermal MC38 tumor model, cyclodextrin-modified macrin NPs loaded with immunostimulatory drugs significantly reduced tumor growth. Therefore, efficient and effective repolarization of tumor-associated macrophages to an M1-like phenotype-via drug-loaded macrins-inhibits tumor growth and may be useful as an adjuvant to existing immune checkpoint therapies.

We found that combination therapy using the MER tyrosine kinase (MERTK) inhibitor UNC2025 and the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) effectively decreased meningioma spheroid viability and proliferation. Furthermore, we demonstrated this combination therapy significantly increased the expression of the epithelial marker E-cadherin and had a repressive effect on WHO grade 2-derived spheroid invasion, which is suggestive of a partial reversal of EMT in meningioma spheroids.

Arid3a promotes cholestatic liver injury by impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes by macrophages during cholestasis. The Arid3a-Mertk axis is a promising novel therapeutic target for cholestatic liver diseases.

Inhibition of MERTK with the small-molecule inhibitor UNC2025 results in reduced proliferation of DSRCT cells in vitro, suggesting MERTK as a therapeutic target in DSRCT. This study underscores the usefulness of preclinical in vitro models for studying molecular mechanisms and potential therapeutic options.

The more selective MerTK inhibitors UNC2250 and UNC2580A lack the anti-proliferative potency of less-selective inhibitors exemplified by UNC2025...Gene expression analysis from cohorts of glioblastoma patients identified that MerTK expression correlates negatively with proliferation and positively with quiescence genes, suggesting that MerTK regulates dormancy rather than proliferation in glioblastoma. In summary, this study demonstrates the importance of orthogonal inhibitors and disease-relevant models in target validation studies and raises a possibility that MerTK inhibitors could be used to target dormant glioblastoma cells.

To assess our results, we are validating AXL, TYRO3 and MERTK expression by immunohistochemistry in a large cohort of patients with III-IV stage melanoma. Moreover, studies reported the molecule UNC2025 as a specific MerTK inhibitor, suggesting that MerTK receptor could also represent a potential therapeutic target for advanced melanoma.

To assess our results, we are validating AXL, TYRO3 and MERTK expression by immunohistochemistry in a large cohort of patients with III-IV stage melanoma. Moreover, studies reported the molecule UNC2025 as a specific MerTK inhibitor, suggesting that MerTK receptor could also represent a potential therapeutic target for advanced melanoma.

To assess our results, we are validating AXL, TYRO3 and MERTK expression by immunohistochemistry in a large cohort of patients with III-IV stage melanoma. Moreover, studies reported the molecule UNC2025 as a specific MerTK inhibitor, suggesting that MerTK receptor could also represent a potential therapeutic target for advanced melanoma.

Both long‑term and short‑term effects of natural PS overexpression were comparable to the treatment of the cells with the drug UNC2025, which inhibits the Mer‑receptor. The present study lays the foundation for investigation of PS as a therapeutic agent to control cancer progression and to concurrently arrest thrombotic events.