hmpl-013 and Disease-Models--Animal

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; CD8 Antigens; Cell Line, Tumor; Chemotherapy, Adjuvant; Colectomy; Colorectal Neoplasms; Disease Models, Animal; Drug Synergism; Humans; Immune Checkpoint Inhibitors; Male; Mice; Mice, Knockout; Microsatellite Instability; Programmed Cell Death 1 Receptor; Quinazolines; Receptors, Vascular Endothelial Growth Factor; T-Lymphocytes, Regulatory; Treatment Outcome; Tumor Microenvironment; Young Adult

Wet age-related macular degeneration, which is characterized by choroidal neovascularization (CNV) and induces obvious vision loss. Vascular endothelial growth factor (VEGF) family member VEGF-A (also named as VEGF) and its receptor VEGFR2 contribute to the pathogenesis of CNV. Choroidal endothelial cells (CECs) secret C-C motif chemokine ligand 2 (CCL2), which attracts macrophages to CNV lesion and promotes macrophage M1 polarization. Accordingly, infiltrating macrophages secret inflammatory cytokines to promote CNV. In vivo, intravitreal injection of fruquintinib (HMPL-013), an antitumor neovascularization drug, alleviated mouse CNV formation without obvious ocular toxicity. Meanwhile, HMPL-013 inhibited VEGF/VEGFR2 binding in CECs and macrophages, as well as macrophage M1 polarization. In vitro, noncontact coculture of human choroidal vascular endothelial cells (HCVECs) and macrophages under hypoxia conditions was established. HMPL-013 downregulated VEGF/VEGFR2/phosphoinositide-3-kinase/protein kinase B (AKT)/nuclear factor kappa B pathway and CCL2 secretion in HCVECs, as well as VEGF/VEGFR2-induced macrophage M1 polarization under hypoxia condition. In addition, HMPL-013 inhibited HCEVC derived CCL2-induced macrophage migration and M1 polarization, along with macrophage M1 polarization-induced HCVECs proliferation, migration, and tube formation. Altogether, HMPL-013 alleviated CNV formation might via breaking detrimental cross talk between CECs and macrophages.

Topics: Animals; Benzofurans; Cell Movement; Cell Proliferation; Choroidal Neovascularization; Disease Models, Animal; Endothelial Cells; Humans; Macrophages; Male; Mice; Mice, Transgenic; Quinazolines; Vascular Endothelial Growth Factor A

VEGF/VEGFR signal axis has been proven to be an important target for development of novel cancer therapies. One challenging aspect in small molecular VEGFR inhibitors is to achieve sustained target inhibition at tolerable doses previously seen only with the long-acting biologics. It would require high potency (low effective drug concentrations) and sufficient drug exposures at tolerated doses so that the drug concentration can be maintained above effective drug concentration for target inhibition within the dosing period. Fruquintinib (HMPL-013) is a small molecule inhibitor with strong potency and high selectivity against VEGFR family currently in Phase II clinical studies. Analysis of Phase I pharmacokinetic data revealed that at the maximum tolerated dose of once daily oral administration fruquintinib achieved complete VEGFR2 suppression (drug concentrations were maintained above that required to produce >85% inhibition of VEGFR2 phosphorylation in mouse) for 24 hours/day. In this article, the preclinical data for fruquintinib will be described, including kinase enzyme activity and selectivity, cellular VEGFR inhibition and VEGFR-driven functional activity, in vivo VEGFR phosphorylation inhibition in the lung tissue in mouse and tumor growth inhibition in a panel of tumor xenograft and patient derive xenograft models in mouse. Pharmacokinetic and target inhibition data are also presented to provide a correlation between target inhibition and tumor growth inhibition.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Epithelial Cells; Female; Humans; Inhibitory Concentration 50; Mice; Phosphorylation; Protein Kinase Inhibitors; Quinazolines; Signal Transduction; Tumor Burden; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3; Xenograft Model Antitumor Assays