ASLAN002

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.

We validated the targeted therapeutic effects of RON and MET in TNBC using three tyrosine kinase inhibitors (TKIs): BMS-777607, INCB28060, and tivantinib. RON and MET co-overexpression can be significant pathological characteristics in TNBC for poor prognosis. TKIs targeting RON and MET have stronger drug development potential for treating TNBC.

Pro-inflammatory cytokines increased with combinational treatment. Together these studies indicate that pan-TAM inhibitor BMS-777607 cooperates with anti-PD-1 in a syngeneic mouse model for triple-negative breast cancer and highlights the clinical potential for this combined therapy.

Four human pancreatic cancer cell lines expressing variable levels of RON or MET and four MET superfamily inhibitors (BMS777607, PHA665752, INCB28060, Tivantinib) were used. RON and MET can be important indicators of prognosis in pancreatic cancer. Tyrosine kinase inhibitors targeting RON and MET in pancreatic cancer are a novel and potential approach for pancreatic cancer therapy.