UNC2025 / University of North Carolina-Chapel Hill - LARVOL DELTA

MerTK is Ectopically Expressed and Affects the Biological Function in Diffuse Large B-Cell Lymphoma. (PubMed, Hematol Oncol) - "Targeted knockdown of MerTK or application of UNC2025, a small inhibitor of MerTK, can inhibit DLBCL cell proliferation, promote apoptosis, and inhibit G2/M phase arrest...Therefore, MerTK is ectopically expressed in DLBCL, and targeted inhibition of MerTK suppresses the growth of DLBCL in vitro and in vivo. This study provides clues for precision therapy for DLBCLs that target MerTK."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ANXA1 • MERTK

A Disintegrin and Metalloproteinase 17 Disrupts Bovine Macrophage MER Proto-Oncogene Tyrosine Kinase Integrity to Impede Apoptotic Cell Clearance and Promote Inflammation in Clinical Mastitis. (PubMed, J Agric Food Chem) - "Silencing MERTK interrupted efferocytosis, a phenomenon also observed with the inhibition of MERTK phosphorylation by UNC2025, which concurrently suppressed anti-inflammatory cytokine production. These findings suggest that targeting the MERTK-ADAM17 axis could enhance inflammatory resolution, providing a novel therapeutic strategy for dairy cattle health management."

Journal • Inflammation • Oncology • ADAM17 • CD163 • MERTK

Protein S Enhances the Phagocytosis of Phosphatidylserine-Positive Erythrocyte: Implications for the Erythrocytes Turnover (ASH 2024) - "CFSE-labelled Iono-RBC or eryghosts were added to THP-1-derived macrophages in the presence or absence of ProS (50 or 100 nM) and of a MerTK inhibitor (UNC2025, 5µM)...ProS may be trapped on the surface of circulating eryghosts, worsening coagulation's ongoing activation. Hence, ProS may be an interesting target for future treatments in hemolytic anemias such as SCD."

Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CD14 • CSF1 • GYPA • IL10 • MERTK • NDUFA2 • PROS1

Extracellular vesicles containing GAS6 protect the liver from ischemia-reperfusion injury by enhancing macrophage efferocytosis via MerTK-ERK-COX2 signaling. (PubMed, Cell Death Discov) - "Knockdown of GAS6 via lentiviral transfection or inhibition of MerTK using UNC2025 (a MerTK small molecule inhibitor) partially eliminates the protective effects of MSC-EVs on macrophage efferocytosis and liver injury...In a murine model of HIRI, MSC-EVs enriched GAS6 effectively enhance macrophage efferocytosis both in vivo and in vitro through the GAS6/MerTK/ERK/COX2 signaling pathway and significantly mitigate liver injury. This image was drawn by the authors."

Journal • Cardiovascular • Hepatology • Inflammation • Liver Failure • Reperfusion Injury • Transplantation • GAS6 • MERTK

Targeting MERTK on tumour cells and macrophages: a potential intervention for sporadic and NF2-related meningioma and schwannoma tumours. (PubMed, Oncogene) - "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."

Journal • Tumor cell • Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor • FLT3 • GAS6 • MERTK • TYRO3

Osteopontin regulation of MerTK+ macrophages promotes Crohn's disease intestinal fibrosis. (PubMed, iScience) - "OPN upregulated TGF production by altering ERK1/2 phosphorylation, as evidenced by OPN or MerTK knockdown and OPN overexpression in vitro. MerTK inhibitor UNC2025 alleviated intestinal fibrosis in mouse colitis models, suggesting a potential therapeutic target for intestinal fibrosis in patients with CD."

Journal • Crohn's disease • Fibrosis • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • MERTK • SPP1 • TGFB1

Co-targeting JAK1/STAT6/GAS6/TAM signaling improves chemotherapy efficacy in Ewing sarcoma. (PubMed, Nat Commun) - "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."

Journal • Acute Myelogenous Leukemia • Ewing Sarcoma • Oncology • Pediatrics • Sarcoma • Solid Tumor • AXL • GAS6 • JAK1 • MERTK • STAT6

Host-functionalization of macrin nanoparticles to enable drug loading and control tumor-associated macrophage phenotype. (PubMed, Front Immunol) - "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."

Journal • Immunology • Oncology • IL12A • MRC1 • NOS2

Targeting the receptor tyrosine kinase MerTK shows therapeutic value in gastric adenocarcinoma. (PubMed, Cancer Med) - "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."

Journal • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MERTK

Light-Activatable Photocaged UNC2025 for Triggering TAM Kinase Inhibition in Bladder Cancer. (PubMed, Chembiochem) - "The most promising candidate was the N,O-dicaged compound, showing the superiority of having two photolabile protecting groups on UNC2025 for being entirely inactive on TAM kinases. Under UV-light irradiation, the N,O-dicaged compound recovered its inhibitory potency in enzymatic assays and displayed excellent antiproliferative activity in RT112 cell lines."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

A novel patient-derived meningioma spheroid model as a tool to study and treat epithelial-to-mesenchymal transition (EMT) in meningiomas. (PubMed, Acta Neuropathol Commun) - "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."

Journal • Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor • CD163 • CD68 • CDH1 • MERTK

A+T rich interaction domain protein 3a (Arid3a) impairs Mertk-mediated efferocytosis in cholestasis. (PubMed, J Hepatol) - "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."

Journal • Cholestasis • Hepatology • Immunology • Liver Failure • Oncology • Primary Biliary Cholangitis • MERTK

Bacterial outer membrane vesicle based versatile nanosystem boosts the efferocytosis blockade triggered tumor-specific immunity. (PubMed, Nat Commun) - "MerTK inhibitor UNC2025 is loaded into the bacterial outer membrane vesicles (OMVs), which are then modified with maleimide (mU@OMVs). The prepared mU@OMVs effectively inhibits the efferocytosis by promoting the uptake while preventing the MerTK phosphorylation of tumor associated macrophages, and then captures the released antigens through forming universal thioether bonds. The obtained in situ vaccine effectively transfers to lymph nodes by virtue of the intrinsic features of OMVs, and then provokes intense immune responses that can efficiently prevent the growth, metastasis and recurrence of tumors in mice, providing a generalizable strategy for cancer immunotherapy."

Journal • Oncology • MERTK

Therapeutic Targeting of Mertk and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia (ASH 2021) - P1 | "T-ALL patient samples were cultured with UNC2025, a close analogue of MRX-2843, and relative cell numbers were assessed using MTS reagent. These data demonstrate the therapeutic potential of MRX-2843 in patients with T-ALL, suggest that MRX-2843 may be particularly active alone and in combination with venetoclax in the ETP-ALL subset, and provide rationale for clinical testing of MRX-2843, with the ultimate goal to progress to trials evaluating MRX-2843 in combination with other agents. Toward this end, MRX-2843 monotherapy will be tested in patients with relapsed leukemia in an upcoming clinical trial (NCT04872478)."

Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • BCL2 • FLT3 • MERTK

MER Signaling Axis: A Novel Therapeutic Target in Chronic Lymphocytic Leukemia (ASH 2022) - "B-cell receptor (BCR)-signal inhibitors, specifically Ibrutinib which targets Bruton's tyrosine kinase (BTK) and Idelalisib which targets PI3Kδ, are effective in relapsed/refractory CLL patients. Finally, treatment of CLL mice with a high-affinity MER inhibitor (UNC-2025) via oral gavage significantly reduced leukemic tumor burden. In total, our findings suggest that expression/activation of MER may potentiate CLL cell survival via a crosstalk with the BCR signal thus, could be an attractive therapeutic target for the progressive CLL patients."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • AXL • BTK • CD19 • CD5 • CD79A • FCER2 • GAS6 • IGH • LYN • PIK3CD • TCL1A

MerTK-EXPRESSING MACROPHAGES PROMOTE THE MALIGNANT FEATURES OF CHOLANGIOCARCINOMA CELLS (AASLD 2022) - "These effects were reduced by UNC2025, a small molecule inhibitor of MerTK... These data indicate that a cross-talk between MerTK-expressing cells in the stroma and iCCA cells results in increased malignant features. In patients, MerTK expression predicts tumor recurrence."

Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Immune Modulation • Immunology • Inflammation • Oncology • Solid Tumor • GAS6 • ID3 • MERTK • PTPRC

Cross-talk between MerTK-expressing stromal cells and cholangiocarcinoma (EASL-ILC 2022) - "These effects were reduced following macrophage pre-treatment with the MerTK inhibitor, UNC2025... These data suggest a cross-talk between MerTKexpressing cells in the stroma and CCA cells, to induce increased malignant features."

Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • GAS6 • MERTK • PTPRC

Cross-talk between MerTK-expressing stromal cells and Cholangiocarcinoma (LCS 2022) - "These effects were reduced following macrophage pre-treatment with the MerTK inhibitor, UNC2025... These data suggest a cross-talk between MerTK-expressing cells in the stroma and CCA cells, to induce increased malignant features."

Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • GAS6 • MERTK • PTPRC

EWSR1-WT1 Target Genes and Therapeutic Options Identified in a Novel DSRCT In Vitro Model. (PubMed, Cancers (Basel)) - "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."

Journal • Preclinical • Oncology • Pediatrics • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • EWSR1 • MERTK • WT1

Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8 T Cells. (PubMed, Vaccines (Basel)) - "Using ex vivo T cell receptor (TCR)-activated CD8 T cells, we demonstrate that use of dual MERTK/FLT3 inhibitor UNC2025 restricts CD8 T proliferation at the G2 phase, at least in part by modulation of mTOR signaling. Finally, we show that activated CD8 T cells express FLT3 from day two post activation, and FLT3 inhibition with AC220 (quizartinib) or siRNA-mediated knockdown affects cell cycle kinetics. These results signify that caution is needed when using potent RTKIs in the context of antitumor immune responses."

IO biomarker • Journal • Oncology • CD8 • FLT3 • MERTK

[VIRTUAL] TAM receptors as potential therapeutic targets in NF2-related schwannomas and meningiomas (AACR 2021) - "Pathological proliferation and survival of both cell types were successfully reversed by AXL inhibitor BGB324 (BerGenBio, FDA approved for AML) and MERTK inhibitor UNC2025 (preclinical) in vitro, with UNC2025 being more effective. Our findings suggest that TAM receptors are aberrantly expressed and activated in human Merlin-deficient meningiomas and schwannomas. Infiltration of M2 macrophages may contribute to an overall increase in the expression of TAM receptors in these tumors. AXL and MERTK are important in schwannoma and meningioma pathogenesis and are potentially good therapeutic targets."

Acute Myelogenous Leukemia • Meningioma • Oncology • Solid Tumor • CD163 • MERTK • NF2

MerTK activity is not necessary for the proliferation of glioblastoma stem cells. (PubMed, Biochem Pharmacol) - "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."

Journal • Glioblastoma • Oncology • Solid Tumor • MERTK

[VIRTUAL] Data mining on transcriptomic data unmasks AXL, TYRO3 and MERTK receptors as new potential prognostic markers for advanced cutaneous melanoma: an ongoing project (ECP 2020) - "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."

Biomarker • Cutaneous Melanoma • Immune Modulation • Immunology • Inflammation • Melanoma • Oncology • Solid Tumor • AXL • CD8 • MERTK

[VIRTUAL] Data mining on transcriptomic data unmasks AXL, TYRO3 and MERTK receptors as new potential prognostic markers for advanced cutaneous melanoma: an ongoing project (ECP 2020) - "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."

Biomarker • Cutaneous Melanoma • Immune Modulation • Immunology • Inflammation • Melanoma • Oncology • Solid Tumor • AXL • CD8 • MERTK

[VIRTUAL] Data mining on transcriptomic data unmasks AXL, TYRO3 and MERTK receptors as new potential prognostic markers for advanced cutaneous melanoma: an ongoing project (ECP 2020) - "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."

Biomarker • Cutaneous Melanoma • Immune Modulation • Immunology • Inflammation • Melanoma • Oncology • Solid Tumor • AXL • CD8 • MERTK