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.

References:
1. Yu, Y.; et. al. Exploratory biomarker discovery for clinical development of ARQ 087, a potent pan-FGFR kinase inhibitor. Cancer Res 2011, 71(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 2010, 8(7), 44-45.
3. Shaw, A. T.; et. al. Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Revs Cancer 2013, 13, 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)

Drugs in Clinical Pipeline: Lucitanib

Lucitanib [6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide] is an oral, potent inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors 1 through 3 (FGFR-1,2,3), vascular endothelial growth factor receptors 1 through 3 (VEGFR-1,2,3) and platelet-derived growth factor receptors alpha and beta (PDGFR- a,ß). As an inhibitor of FGFR-1,2,3, VEGFR-1,2,3 and PDGFR a/ß, and the role that each of these receptor kinases plays in tumor progression and metastasis formation, Lucitanib has the potential benefit of targeting three relevant pro-angiogenic growth factors in targeted patient populations identified by molecular markers.

Clovis Oncology holds exclusive development and commercial rights to lucitanib on a global basis, excluding China. Lucitanib rights to markets outside of the U.S. and Japan have been sublicensed to Les Laboratoires Servier (Servier).

Common Name: Lucitanib
Synonyms: CO-3810; S 80881; E-3810

IUPAC Name: 6-({7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl}oxy)-N- methylnaphthalene-1-carboxamide

CAS Number: 1058137-23-7
Mechanism of Action: Kinase Inhibitor; FGFR Inhibitor; VEGFR Inhibitor; PDGFR Inhibitor
Indication: Various cancers, tumors
Development Stage: Phase I/II

Company: Clovis Oncology

A Phase I/IIa clinical trial of Lucitanib was initiated in 2010 and has demonstrated multiple objective responses in FGFR1 gene-amplified breast cancer patients, and objective responses were also observed in patients with tumors often sensitive to VEGFR inhibitors, such as renal cell and thyroid cancer. FGFR amplification is common in a number of tumor types, including breast cancer and lung cancer, and it is intended to study Lucitanib in these cancers as well as other solid tumors exhibiting FGFR pathway activation. A broad Phase II development program has been initiated by Clovis and Servier in multiple indications, including advanced breast and lung cancers.