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

Aberrant expression of MERTK activates BCR via CD79a in CLL cells: alternative therapeutic strategy for relapsed/refractory CLL. (PubMed, Leukemia) - "More significantly, ibrutinib-resistant CLL cells expressed high-levels of MERTK and that, UNC-2025 synergistically induced apoptosis when combined with venetoclax. Thus, high MERTK-levels in CLL cells may be associated with ibrutinib-resistance underscoring the potential use of UNC-2025/venetoclax combination in treating relapsed/refractory patients."

Journal • Chronic Lymphocytic Leukemia • AXL • CD79A • GAS6 • LYN • MERTK

NLRC5-Deficient Macrophages Promote a Tumor-Permissive Phenotype via AXL- and MERTK-Mediated Efferocytosis. (PubMed, FASEB J) - "Pretreatment of macrophages with AXL and MERTK inhibitors (R428, UNC2025) resulted in reduced efferocytosis and phosphorylation of downstream signaling molecules, STAT3 and ERK1/2. We propose that defective NLRC5 signaling in macrophages leads to tumor-permissive responses, thereby promoting the development of gastric lymphoid neogenesis to Helicobacter infection."

Journal • B Cell Lymphoma • Gastric Cancer • Hematological Malignancies • Infectious Disease • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • AXL • CD8 • IL10 • MERTK • NLRC5 • SOCS1 • SOCS3 • STAT3 • TGFB1

Noninvasive deciphering of the immunosuppressive tumor microenvironment and evaluation of MerTK inhibitor mediated reversal of ICB resistance via MerTK-targeted PET. (PubMed, Bioorg Chem) - "An ICB-resistant B16F10 melanoma tumor model was established, and we further verified that the combined treatment with MerTK inhibitor UNC2025 and anti-mouse PD-1 recombinant mAb effectively restored the ICB treatment efficacy...Our findings indicate that [68Ga]Ga-MerTKi PET can potentially identify patients who may benefit from ICB therapy alone and who may need combination therapy. This observation supports the use of MerTK PET as a tool to guide more personalized treatment in cancer immunotherapy."

Biomarker • IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • MERTK

Shengxian Decoction mitigate bleomycin-induced pulmonary fibrosis in mice via MerTK mediated macrophage efferocytosis. (PubMed, J Ethnopharmacol) - "SXD confered multi-target protection in BLM-induced pulmonary fibrosis and promoted resolution by enhancing macrophage apoptotic-cell clearance through a MerTK-dependent mechanism, which supported its translational potential for the intervention of IPF."

Journal • Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CD68 • IL10 • IL1B • IL6 • MERTK • TGFB1 • TNFA

AXL inhibition as an immune-enabling targeted therapy for glioblastoma (SNO 2025) - "In an expanded analysis, comparison across four GSC lines treated with a panel of AXL inhibitors including BMS777607, bemcentinib, ONO-7475, and UNC2025 revealed differential effects on cell viability and proliferation. In conclusion, AXL inhibitors alter gene expression in a similar fashion to EGFR and BRAF inhibitors, differentially kill GSCs, reduce cell proliferation, and differentially alter macrophage immunophenotypes. This work suggests that the choice of AXL inhibitor is critically important when considering effects on the tumor immune milieu and on GBM growth suppression."

Brain Cancer • Glioblastoma • Solid Tumor • EGFR

AXL inhibition as an immune-enabling targeted therapy for glioblastoma (WFNOS 2025) - "In an expanded analysis, comparison across four GSC lines treated with a panel of AXL inhibitors including BMS777607, bemcentinib, ONO-7475, and UNC2025 revealed differential effects on cell viability and proliferation. In conclusion, AXL inhibitors alter gene expression in a similar fashion to EGFR and BRAF inhibitors, differentially kill GSCs, reduce cell proliferation, and differentially alter macrophage immunophenotypes. This work suggests that the choice of AXL inhibitor is critically important when considering effects on the tumor immune milieu and on GBM growth suppression."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • EGFR

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

Targeting MERTK tyrosine kinase: Virtual screening and molecular dynamics insights for anti-cancer drug development. (PubMed, PLoS One) - "We used known compound UNC2025 as positive control and one million compounds was retrieved from different databases (OTAVA, ZINC, ChEMBL) and docked with MERTK protein...The study finds critical residues which serve a vital part in binding with the inhibitor and the active site of the MERTK protein, i.e., Phe598, Gly599, Lys619, Arg629, Glu633, Glu637, Arg722, Asp723, Arg727, Asp741, Gly743, Leu744, Lys746, Arg758, Ala760, and Lys761 through decomposed binding free energy analysis. This study focuses on the pursuit of several MERTK protein targets, which could have consequences for the development of novel therapeutics for various cancers."

Journal • Acute Myelogenous Leukemia • Breast Cancer • Epithelial Ovarian Cancer • Hematological Malignancies • Leukemia • Liver Cancer • Melanoma • Oncology • Ovarian Cancer • Solid Tumor • LIG3 • LRIG1 • MERTK

Engineered biomimetic vesicles induce cuproptosis and disrupt efferocytosis for metastatic adenoid cystic carcinoma immunotherapy. (PubMed, Mater Today Bio) - "CG/MC/U-M was derived from ACC cell membranes, encapsulating carbonyl manganese (Mn2(CO)10), efferocytosis inhibitor (UNC2025) and metal-phenolic network (CuGA)...This dual-action mechanism synergistically reprogramed the immunosuppressive microenvironment, promoting the maturation of dendritic cells (DCs), repolarizing macrophages to the M1 phenotype, and resulting in a significant increase in the infiltration of CD8+ T cells. Both in vitro and in vivo studies indicated that the CG/MC/U-M system effectively targeted ACC pulmonary metastases and inhibited ACC progression within lung tissues, underscoring its potential for personalized adenoid cystic carcinoma (ACC) therapy."

Journal • Adenoid Cystic Carcinoma • Oncology • Salivary Gland Cancer • Solid Tumor

Targeting the ANXA8-SP1-PPA1 Axis to Modulate TCA Cycle and Matrix Deposition in Diffuse-Type Gastric Cancer. (PubMed, Research (Wash D C)) - "Deletion of ANXA8 suppresses malignant phenotypes and shows synergistic effects with the chemotherapeutic agent 5-fluorouracil (5-FU). Furthermore, a polyphenol-based UNC2025 nanodelivery system improved the efficacy of this combination therapy. In summary, this study elucidates how ANXA8-mediated suppression of the TCA cycle promotes dense ECM formation and malignant progression in DGC, highlighting the therapeutic potential of targeting ANXA8 in DGC treatment."

Journal • Gastric Cancer • Oncology • Solid Tumor

Hydroxychloroquine enhances efferocytosis and modulates inflammation via MerTK/Gas6 signaling in a pristane-induced lupus mouse model. (PubMed, Front Immunol) - "The role of MerTK on HCQ-modulated inflammation was revealed by MerTK inhibitor UNC2025. HCQ-induced anti-inflammatory markers, such as PPARγ, LXR, and IL-10, were also alleviated upon MerTK blockade. This study provides robust in vitro and in vivo evidence that HCQ promotes macrophage efferocytosis and anti-inflammatory reprogramming via MerTK/Gas6 signaling, offering insights into potential therapeutic mechanisms in SLE management."

Journal • Preclinical • Glomerulonephritis • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Rheumatoid Arthritis • Rheumatology • Sjogren's Syndrome • Systemic Lupus Erythematosus • GAS6 • IFNA1 • IL10 • IL6 • MERTK • PPARG

Glycopolymeric Nanoparticles Block Breast Cancer Growth by Inhibiting Efferocytosis in the Tumor Microenvironment. (PubMed, ACS Appl Nano Mater) - "Lastly, UNC2025-PMAM NPs significantly reduced tumor volume compared to free UNC2025, showing greater therapeutic efficacy in a model of triple-negative breast cancer. These glycopolymer-based, efferocytosis-blocking NPs have promise both as a class of standalone cancer immunotherapy and as an adjuvant to improve response rates to checkpoint immunotherapy."

Biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MERTK • MRC1

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

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