ASLAN002

Subsequent optimization yielded A30, a hybrid scaffold inhibitor demonstrating potent activity against both wild-type and mutant c-Met, comparable to the reference inhibitor BMS-777607. Cellular assays revealed that A30 significantly suppressed proliferation, migration, and colony formation in NCI-H1993 and HCT-116 cells, while inducing apoptosis. These findings highlight A30 as a promising lead compound for targeting c-Met-driven resistance.

Furthermore, BMS777607, a receptor tyrosine kinase inhibitor capable of repolarizing M2 macrophages in vitro, reduced organoid viability via a macrophage-dependent mechanism...A TAM-targeted CSF-1 R inhibitor, BLZ945, combined with paclitaxel reduced tumor burden with no regrowth, suggesting that TAMs promote paclitaxel resistance in this model. Our study demonstrates that TAMs influence response to paclitaxel in both patient-derived OC organoids and huPDX. These models are useful for evaluating immunomodulatory therapy effects and could serve as a robust platform for preclinical testing of novel anti-cancer treatments, providing insights into the complex interplay between immune cells and cancer therapeutics.

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.

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.

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.

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.

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.

BMS-777607 can inhibit proliferation and promote apoptosis of CAL27 cells.

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.