Tuesday, April 21, 2015

Drugs in Clinical Pipeline: ARQ-087

ARQ-087 is an orally available multi-kinase inhibitor designed to preferentially inhibit the fibroblast growth receptor (FGFR) family. ARQ 087 binds to and potently inhibits the activity of FGFR subtypes 1, 2 and 3 [1-3].  FGFR, a receptor tyrosine kinase, is upregulated in many tumor cell types and plays a key role in tumor cellular proliferation, differentiation, angiogenesis and survival.
ARQ-087 inhibits FGFR-1, 2, and 3 with IC50 values in the 2-4 nM range, with FGFR4 being inhibited 10-fold less potently. ARQ 087 displayed inhibition kinetics that were ATP-independent, while showing a 20-fold preference for inactive FGFR2 in biochemical assays. Concentration dependent inhibition of phosphorylation of downstream FGFR signals (FRS, MEK, ERK, and AKT) is evident in response to ARQ-087 treatment.

In cell-based assays, ARQ 087 showed potent inhibition of FGFR2 phosphorylation with IC50 values of 150 and 45 nM in KATO III and SNU-16 human gastric carcinoma cells, respectively. The corresponding antiproliferative potencies (GI50) by MTS assay were reported as 130 and 690 nM, respectively.
ARQ-087 is in Phase I dose escalation study for patients with solid tumors [4]. Moreover, ArQule is currently conducting a biomarker-driven phase 2 trial for ARQ-087 in the U.S. and Italy in intrahepatic cholangiocarcinoma (iCCA) patients with FGFR2 fusions. 

In Dec 2015, ArQule, Inc. announced receipt of orphan drug designation from the Food and Drug Administration (FDA) for ARQ 087 in cholangiocarcinoma.

1. Yu, Y.; et. al. Exploratory biomarker discovery for clinical development of ARQ 087, a potent pan-FGFR kinase inhibitor. Cancer Res 201171(Suppl. 1), 3571.
2. Chen, C. R.; et. al. 119 ARQ 087: A potent ATP-independent fibroblast growth factor receptor (FGFR) kinase inhibitor showing in vivo anti-tumor activity in FGFR2-driven tumors. EJC Supplements 20108(7), 44-45.
3. Shaw, A. T.; et. al. Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Revs Cancer 201313, 772–787.
4. ClinicalTrials.gov Phase 1 Dose Escalation Study of ARQ 087 in Adult Subjects With Advanced Solid Tumors. NCT01752920 (retrieved 21-04-2015)