ASLAN002 / BMS - LARVOL DELTA

GPX4-mediated Pathway Regulates Iron Efflux to Prevent Ferroptotic Cell Death and Promote Immunosuppressive Signals in Osteosarcoma Cells (AACR 2025) - "Erastin, an xCT inhibitor, and RSL3, a GPX4 inhibitor, induced ferroptotic cell death in these cells...We observed that combination treatment with dual MSPR and MET inhibitor, BMS-777607, showed synergistic effects with GPX4 inhibition...We also identified novel target, MSPR, regulated by GPX4 inhibition, which potentially contribute to the activation of immunosuppressive signals from osteosarcoma. In conclusion, this study underscores that targeting the ferroptotic pathway holds a great promise for therapeutic potential in osteosarcoma by regulating both intracellular pathway and the immunosuppressive tumor microenvironment."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • AKR1C1 • FTH1 • GPX4 • HMOX1 • NQO1

Identification of a 7H-pyrrolo[2,3-d]pyrimidin derivatives as selective type II c-Met/Axl inhibitors with potent antitumor efficacy. (PubMed, Bioorg Chem) - "Through a systematic exploration of the structure-activity relationship, based on the clinically reported c-Met inhibitor BMS-777607, we identified the optimized compound 22a...In established MKN-45 and HCT116 xenograft tumor models, compound 22a achieved tumor growth inhibition (TGI) rates of 98.2 % and 87.2 %, respectively, at a dosage of 1 mg/kg. Taken together, compound 22a is a selective dual c-Met/Axl inhibitor with significant potential as a clinical candidate."

Journal • Oncology • Solid Tumor • MET

Coordinated targeting of S6K1/2 and AXL disrupts pyrimidine biosynthesis in PTEN-deficient glioblastoma. (PubMed, Cancer Res Commun) - "Kinome-wide ATP binding analysis in inhibitor-treated cells revealed that LY-2584702 directly inhibited S6K1, and substrate phosphorylation studies showed that BMS-777607 inactivation of upstream AXL collaborated to reduce S6K2-mediated signal transduction. Thus, combination targeting of S6K1 and AXL provides a kinase-directed therapeutic approach that circumvents signal transduction redundancy to interrupt metabolic function and reduce growth of PTEN-deficient GBM."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • AXL • PTEN • RPS6

Efferocytosis Nanoinhibitors to Promote Secondary Necrosis and Potentiate the Immunogenicity of Conventional Cancer Therapies for Improved Therapeutic Benefits. (PubMed, ACS Nano) - "Herein, a nanoparticulate inhibitor of efferocytosis is prepared by encapsulating BMS777607, a hydrophobic inhibitor of receptors in macrophages responsible for phosphatidylserine-dependent efferocytosis, with biocompatible poly(lactic-co-glycolic acid) and its amphiphilic derivatives...As a result, intratumorally injected nano-BMS is capable of activating both innate and adaptive antitumor immunity to achieve greatly improved therapeutic responses, when synergized with nonimmunogenic chemotherapy by cisplatin, immunogenic chemotherapy by oxaliplatin, or radiotherapy by external beams. Moreover, we further demonstrate that the inhalation of nano-BMS could significantly promote the efficacy of cisplatin chemotherapy to suppress tumor lung metastases. Therefore, this study highlights a general strategy to potentiate the immunogenicity of different cancer treatments by suppressing efferocytosis-propelled tumor immunosuppression, showing tremendous clinical potential in..."

Journal • Oncology

Design, synthesis and biological evaluation of 4-(4-aminophenoxy)picolinamide derivatives as potential antitumor agents. (PubMed, Eur J Med Chem) - "In this study, a total of 36 derivatives of 4-(4-aminophenoxy)pyridinamide were designed and synthesized, based on the analysis of the binding patterns of cabozantinib and BMS-777607 to MET protein...In addition, compound 46 also showed good pharmacokinetic characteristics in rats. In conclusion, compound 46 is a promising antitumor agent."

Journal • Oncology • MET

RON-augmented cholesterol biosynthesis in breast cancer metastatic progression and recurrence. (PubMed, Oncogene) - "BMS777607, a RON inhibitor, abrogated CTC colony formation tumor cells and tumor recurrence...In mouse models with RON overexpression, statin-mediated inhibition of cholesterol biosynthesis impeded metastatic progression and recurrence but does not affect the primary tumor. RON upregulates glycolysis and cholesterol biosynthesis gene expression by two pathways: MAPK-dependent c-Myc expression and β-catenin -dependent SREBP2 expression."

Journal • Metastases • Breast Cancer • Oncology • Solid Tumor • CTCs • CTNNB1 • MYC

Repurposing Axl Kinase Inhibitors for the Treatment of Respiratory Syncytial Virus Infection. (PubMed, Antimicrob Agents Chemother) - "Axl inhibition with kinase inhibitors, including BMS-777607, R428, and TP-0903, or Axl ablation resulted in a significant reduction of RSV infection in cell-based assays. We found that Axl inhibition led to more robust IFN-β expression and antiviral gene induction. Thus, the results of this study imply that Axl kinase inhibitors may possess a broad spectrum of antiviral effects by promoting ISG expression."

Journal • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • AXL • IFNB1 • MERTK

Pharmacological inhibition of protein tyrosine kinases axl and fyn reduces TNF-α-induced endothelial inflammatory activation in vitro. (PubMed, Front Pharmacol) - "Upon pharmacological inhibition with each inhibitor, leukocyte adhesion to HUVEC was also significantly reduced, however to a minor extent. In conclusion, pre-treatment of endothelial cells with kinase inhibitors BMS-777607 and PP2 reduces TNF-α-induced endothelial inflammation in vitro."

Journal • Preclinical • Acute Kidney Injury • Immunology • Inflammation • Nephrology • Oncology • Renal Cell Carcinoma • Renal Disease • AXL • CD31 • CXCL8 • ICAM1 • IL6 • PECAM1 • TNFA • VCAM1

Exploiting a negative feedback loop linking S6 Kinases and AXL to reduce pyrimidine biosynthesis in PTEN-deficient glioblastoma (SNO 2022) - "Combining the AXL inhibitor BMS-777607 with S6K1 inhibitor LY-2584702 also prevented compensatory AXL signaling and triggered cytotoxic responses selectively in the PTEN-deficient condition...The oral inhibitors of S6K1 and AXL were found to be brain-penetrant and effective in reducing GBM growth in several mouse models. These results establish that targeting of AXL can circumvent S6 Kinase dependent feedback to reduce pyrimidine biosynthesis and trigger cytotoxic responses in PTEN-deficient GBMs."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • AXL • PTEN

Assessment of the Immune Response to Tumor Cell Apoptosis and Efferocytosis. (PubMed, Methods Mol Biol) - "In the days following lapatinib treatment, agents that block efferocytosis such as BMS-777607 are administered. Tissue is collected from cohorts of mice at day 2 (after lapatinib treatment only) to assess apoptosis, day 8 (after lapatinib treatment followed by blockade of efferocytosis) to assess the immune response to apoptosis and efferocytosis, and day 28 (after 4 consecutive weeks of treatment) to assess therapeutic efficacy. This model enables mechanistic studies of tumor immunology in residual disease as well as therapeutic efficacy studies of targeted agents that disrupt efferocytosis."

Journal • Breast Cancer • HER2 Breast Cancer • Immunology • Inflammation • Oncology • Solid Tumor

RON Receptor Tyrosine Kinase in Tumorigenic Stemness as a Therapeutic Target of Antibody-Drug Conjugates for Eradication of Triple-Negative Breast Cancer Stem Cells. (PubMed, Curr Cancer Drug Targets) - "Sustained RON expression contributes to TNBC-SLC tumorigenesis. Zt/g4-MMAE is effective in vivo in killing TNBC-SLC-mediated xenograft tumors. Our findings highlight the feasibility of Zt/g4-MMAE for eradication of TNBC-SLCs in the future."

Cancer stem cells • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD24 • CD44

Effect of Met kinase inhibitor BMS-777607 on proliferation and apoptosis of tongue cell line CAL 27 squamous cell carcinoma (PubMed, Shanghai Kou Qiang Yi Xue) - "BMS-777607 can inhibit proliferation and promote apoptosis of CAL27 cells."

IO biomarker • Journal • Preclinical • Oncology • Squamous Cell Carcinoma • Tongue Carcinoma • BCL2 • CASP3

Development of bone-targeted Ron inhibitors to treat osseous metastases from breast cancers (AACR 2022) - "In this study, we have developed several bis(phosphonate) or phosphate conjugates of BMS-777607 and LY2801653, and report their accumulation in the bone microenvironment along with effects on osteolysis and tumor burden. We have utilized novel synthetic schemes for synthesis of the drug conjugates. Targeting RON kinase in the bone microenvironment is a promising approach to alleviate morbidities observed in breast cancer patients with bone metastases. We present novel bone-targeting conjugates of BMS-777607 and highlight the potential for clinical development."

Breast Cancer • Oncology • Solid Tumor

Kinase-directed inhibition of pyrimidine biosynthesis in PTEN-deficient glioblastoma (SNO 2021) - "Here we show brain-penetrant inactivation of S6K1 and TAM-RTKs using the S6K1 inhibitor LY-2584702 and the TAM-RTK inhibitor BMS-777607, which reduced glioblastoma tumor growth...Steady-state metabolomics revealed that combined inactivation of S6K1 and TAM-RTKs resulted in decreased nucleotide biosynthesis, and flux analysis indicated reduced flux of glucose to pyrimidines. Altogether the results indicate a kinase-directed therapeutic strategy for targeting S6K1 and TAM-RTKs to reduce pyrimidine biosynthesis and glioblastoma tumor growth."

Brain Cancer • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Glioblastoma • Oncology • Pancreatic Cancer • Solid Tumor • AXL • MERTK • PTEN

RON Mediates Tumor-Promoting Effects in Endometrial Adenocarcinoma. (PubMed, Biomed Res Int) - "RON overexpression could promote growth of endometrial adenocarcinoma cells in nude mice, while its inhibitor BMS777607 could restrict this role. RON played an important role in endometrial adenocarcinoma and had a potential to become a new therapeutic target for endometrial adenocarcinoma."

Journal • Endometrial Adenocarcinoma • Endometrial Cancer • Gynecologic Cancers • Oncology • Solid Tumor • Transplantation

TAM kinase signaling is indispensable for proper skeletal muscle regeneration in mice. (PubMed, Cell Death Dis) - "Administration of the TAM kinase inhibitor BMS-777607 to wild type mice mimicked the effect of Mer ablation on the muscle regeneration process, but in addition, it resulted in a long-persisting necrotic area. Finally, in vitro inhibition of TAM kinase signaling in C2C12 myoblasts resulted in decreased viability and in impaired myotube growth. Our work identifies Axl as a survival and growth receptor in the mouse myoblasts, and reveals the contribution of TAM kinase-mediated signaling to the skeletal muscle regeneration both in macrophages and in myoblasts."

Journal • Preclinical • Fibrosis • Immunology • Inflammation • AXL • PTPRC

[VIRTUAL] Co-targeting c-Met and c-Src pathways to inhibit metastatic cancer cell migration and invasion (AACR 2021) - "In order to delineate this hypothesis, we studied treatment effects of combining inhibitors targeting c-Src (dasatinib) and c-Met (ASLAN002) on multiple functional behaviors associated with tumor metastasis in c-Src and c-Met expressing metastatic cancer cells. Western blot analysis demonstrated that co-targeting Met and Src kinases lead to not only inhibition on c-Met and c-Src autophosphorylation but also multiple downstream kinases such as focal adhesion kinase (FAK), Akt and extracellular signal-regulated kinase (ERK). These data indicate that combined application of small molecule Src and Met inhibitors cause significant impairment on functional behaviors associated with cancer metastasis in vitro including survival, migration and invasion, suggesting that this combination intervention modality may serve as a potential anti-metastatic strategy that could be further tested in metastatic models in vivo."

Oncology • MET

The MSP-RON pathway regulates liver fibrosis through TGF-β-dependent Epithelial-mesenchymal transition. (PubMed, Liver Int) - "Our study revealed that MSP is an important biomarker in liver cirrhosis progression and can be used to prognose patients. The MSP-RON pathway promotes the EMT of hepatocytes and the progress of fibrosis via a TGF-β related pathway. Consequently, we identified a new treatment strategy for liver cirrhosis through targeted inhibition of MSP/RON. This research increases the understanding of EMT-modulated liver fibrosis and provides new insights into biomarkers and therapeutic targets of liver fibrosis. (250 words)."

Journal • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis • TGFB1

Multi-kinase targeted therapy as a promising treatment strategy for ovarian tumors expressing sfRon receptor. (PubMed, Genes Cancer) - "Using human ovarian xenografts and clinically relevant patient-derived xenografts (PDXs), we demonstrated that in vivo treatment with single agent AD80 shows superior efficacy to a standard-care chemotherapy (cisplatin/paclitaxel), or to the direct inhibition of sfRon kinase by BMS777607. Our findings indicate that ovarian tumors expressing sfRon are most effectively treated with multi-kinase inhibitors simultaneously targeting AKT and S6K1, such as AD80, which results in long-term anti-tumor response and prevents metastasis development."

Journal • Oncology • Ovarian Cancer • Solid Tumor

Insensitivity to c-Met inhibition at physiologic HGF concentrations in a prostate carcinoma model (AACR 2018) - "...In our studies, we examined the prostate carcinoma cell line DU145, and BMS-777607...In vitro studies performed at high HGF concentrations may not accurately predict the in vivo drug efficacy. Further characterization of HGF concentrations within the tumor is necessary to properly conduct in vitro evaluation of c-Met inhibitors."

Genito-urinary Cancer • Thyroid Gland Carcinoma

Combination S6K and TAM tyrosine kinase targeting in PTEN-deficient glioma (AACR 2018) - "...Investigating pharmacologic agents, we found that the S6K inhibitor LY-2584702 selectively elicits cytotoxic responses in PTEN-deficient cells when combined with the TAM kinase inactivating agent BMS-777607...Conversely, expression of activated S6K1 or elevated AXL protected from combination treatment. These results indicate that both the TAMS and S6K1 are key regulators of survival in PTEN deficient cells."

Solid Tumor

Enhancement of immune checkpoint PD-1 blockade efficacy in ovarian cancer (AACR 2018) - "BMS-777607 treatment (vs vehicle) did not significantly alter ascites volume.Flow cytometry evaluation of spleen cells showed that in the combination treated mouse group, there was an increase in the average percentage of CD3 (combined treatment group 26.7 vs control 8.5%), CD4 (10.6 vs control 5.0%) and CD8 T cells (10.6 vs control 2.7%). We are investigating changes in immune responses genes in RNA of intestines and livers.ConclusionsAnti-PD-1 antibody treatment is effective in treating ovarian cancer in mice, but treatment with this agent combined with RON/ c-Met inhibitor, BMS-777607 is superior to either single therapy.Combination treatment with these 2 agents holds promise as a novel therapeutic approach for ovarian cancer."

Clinical • Ovarian Cancer

Pathological significance of abnormal recepteur d'origine nantais and programmed death ligand 1 expression in colorectal cancer. (PubMed, World J Gastrointest Oncol) - "RON, PD-L1, and their crosstalk are significant in predicting the prognostic value of CRC. Moreover, phosphorylation of RON upregulates PD-L1 expression, which provides a novel approach to immunotherapy in CRC."

IO Biomarker • Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • PD-L1

[VIRTUAL] S6K FEEDBACK REGULATION OF THE RECEPTOR TYROSINE KINASE AXL IN PTEN-DEFICIENT GLIOBLASTOMA (SNO 2020) - "Previously we established that combining the LY-2584702 inhibitor of S6K1 with the BMS-777607 inhibitor of the AXL receptor tyrosine kinase (RTK) was selectively cytotoxic for PTEN-deficient GBM...Metabolomic analysis revealed combination effects of S6K and AXL inhibitors in reducing nucleotide precursor metabolic flux. We therefore propose that combination inhibition of S6K and AXL signaling compromises S6K-dependent nucleotide synthesis in PTEN-deficient GBM."

Glioblastoma • Oncology • Solid Tumor • AXL • PTEN

A C-Met chemical inhibitor promotes fracture healing through interacting with osteogenic differentiation via the mTORC1 pathway. (PubMed, Exp Cell Res) - "In addition, stimulation of osteoblast differentiation and mineralization was a result of BMS-777607 inducing the expression of Runx2 and Col1, and this osteogenic ability, at least in part, was mediated through the mammalian target of rapamycin complex 1 (mTORC1) signaling in vitro. Conclusively, BMS-777607 has been identified as a therapeutic agent to improve bone formation during fracture healing, and its osteogenic effects on osteoblast differentiation were mediated via the mTORC1 signaling pathway."

Journal • Musculoskeletal Diseases • Osteoporosis