Sunday, August 9, 2015

Drugs in Clinical Pipeline: Fruquintinib

Fruquintinib [6-((6,7-dimethoxyquinazolin-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide] is a novel oral small molecule that selectively inhibits vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 and has demonstrated potent inhibitory effects on multiple human tumor xenografts [1]. In vitro, Fruquintinib demonstrated a highly potent and selective kinase profile against VEGF receptors 1, 2 and 3 (IC50 = 33, 35 and 0.5 nM, respectively). In vivo, Fruquintinib demonstrated broad spectrum anti-tumor activity via oral dosing in multiple tumor xerografts such as BGC-823, BXPC-3 and A375. In low oral doses, Fruquintinib has potent inhibitory effects on multiple human tumor xenografts, including some refractory tumors such as pancreatic cancer and melanoma.

The activity of Fruquintinib is as follows:

IC50 (VEGFR2 enzyme assay) = 35 nM
IC50 (VEGFR3 enzyme assay) = 0.5 nM
IC50 (VEGFR1 enzyme assay) = 33 nM
IC50 (FGFR1 enzyme assay) = 181 nM
IC50 (c-Kit  enzyme assay) = 458 nM
IC50 (Ret enzyme assay) = 128 nM

Common Name: Fruquintinib
Synonyms: AUY HMPL-013; HMPL 013; HMPL013
IUPAC Name: 6-((6,7-dimethoxyquinazolin-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide
CAS Number: 1194506-26-7
Mechanism of Action: Kinase Inhibitor; pan-VEGFR Inhibitor
Indication: Various Cancers; Solid Tumors; Non-small Cell Lung Cancer; Gastric Cancer; Colorectal Cancer
Development Stage: Phase II
Company: Hutchison Medi Pharma (China)/Lilly Inc

Angiogenesis, the process of developing new blood vessels, is critical for tumor cell growth, survival, invasion and metastasis. The vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) play a pivotal role in tumor-related angiogenesis, and the VEGF/VEGFR pathway is an important target for anti-angiogenic drug development and tumor therapy. Inhibition of VEGF signaling in tumor vasculature therefore represents an exciting therapeutic strategy, with the potential to arrest the development of new blood vessels essential for tumor growth and metastasis [2].

Fruquintinib has high permeability without efflux. It shows moderate oral bioavailability of 42-53 % and Tmax less than 4 h in mouse, rat, dog and monkey, with exposure-dose linearity proved in rats and dogs. No significant food effect is on dog pharmacokinetics (PK). Fruquintinib has moderately high tissue distribution. It majorly distributes in gastrointestinal tract, liver, kidney, adrenal and adipose. The plasma protein binding fraction is 88-95 % in mouse, rat, dog and human, invariable up to 10 ┬ÁM. The in vivo clearance of Fruquintinib is low, consistent with the in vitro scaling. Three major oxidative metabolites were identified in liver microsomes of mouse, rat, dog, monkey and human. Fruquintinib has low risk of drug-drug interaction. It is predicted to have favorable human PK properties and low efficacious dose [3]. 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 greater than 85% inhibition of VEGFR2 phosphorylation in mouse) for 24 hours/day [1].            

1. Sun, Q.; et. al. Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol Ther 2014, 15(12), 1635-1645.
2. Sharma, P. S.; et. al. VEGF/VEGFR pathway inhibitors as anti-angiogenic agents: present and future. Curr Cancer Drug Targets. 2011, 11(5), 624-653. (Your's truly is an author here.)
3. Gu, Y.; et. al. Preclinical pharmacokinetics and disposition of a novel selective VEGFR inhibitor fruquintinib (HMPL-013) and the prediction of its human pharmacokinetics. Cancer Chemother Pharmacol 2014, 74(1), 95-115.