title: Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy.
abstract: 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.
authors.affiliation: a Department of Oncology; Hutchison MediPharma Limited ; Shanghai , China ;
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Sun
authors.forename: Jinghong
authors.initials: J
authors.lastname: Zhou
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Mingchuan
authors.initials: M
authors.lastname: Guo
authors.forename: Junqing
authors.initials: J
authors.lastname: Liang
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.forename: Jingwen
authors.initials: J
authors.lastname: Long
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Yin
authors.forename: Huaqing
authors.initials: H
authors.lastname: Cai
authors.forename: Haibin
authors.initials: H
authors.lastname: Yang
authors.forename: Weihan
authors.initials: W
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Gu
authors.forename: Liang
authors.initials: L
authors.lastname: Ni
authors.forename: Yang
authors.initials: Y
authors.lastname: Sai
authors.forename: Yumin
authors.initials: Y
authors.lastname: Cui
authors.forename: Meifang
authors.initials: M
authors.lastname: Zhang
authors.forename: Minhua
authors.initials: M
authors.lastname: Hong
authors.forename: Junen
authors.initials: J
authors.lastname: Sun
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Weiguo
authors.initials: W
authors.lastname: Qing
authors.forename: Weiguo
authors.initials: W
authors.lastname: Su
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Ren
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001572:Benzofurans; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C000591844:HMPL-013; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: 2; 3; AKT, protein kinase B; CAM, chorioallantoic membrane; ERK, extracelluar signal-regulated kinase; KDR, Kinase insert domain-containing receptor, also named as VEGFR2; PI3K, phosphoinositide 3-kinase; PK/PD, pharmacokinetics/pharmacodynamics; PKC, protein kinase C; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; VEGFR1; angiogenesis; anti-tumor activity; cancer treatment; fruquintinib; tumor xenograft models; tyrosine kinase inhibitor