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Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR Dysregulation
Terence G Hall1, Yi Yu1, Sudharshan Eathiraj1
1ArQule, Inc., Burlington, MA, United States of America.
Abstract:
Dysregulation of Fibroblast Growth Factor Receptor (FGFR) signaling through amplifications, mutations, and gene fusions has been implicated in a broad array of cancers (e.g. liver, gastric, ovarian, endometrial, and bladder). ARQ 087 is a novel, ATP competitive, small molecule, multi-kinase inhibitor with potent in vitro and in vivo activity against FGFR addicted cell lines and tumors. Biochemically, ARQ 087 exhibited IC50 values of 1.8 nM for FGFR2, and 4.5 nM for FGFR1 and 3. In cells, inhibition of FGFR2 auto-phosphorylation and other proteins downstream in the FGFR pathway (FRS2α, AKT, ERK) was evident by the response to ARQ 087 treatment. Cell proliferation studies demonstrated ARQ 087 has anti-proliferative activity in cell lines driven by FGFR dysregulation, including amplifications, fusions, and mutations. Cell cycle studies in cell lines with high levels of FGFR2 protein showed a positive relationship between ARQ 087 induced G1 cell cycle arrest and subsequent induction of apoptosis. In addition, ARQ 087 was effective at inhibiting tumor growth in vivo in FGFR2 altered, SNU-16 and NCI-H716, xenograft tumor models with gene amplifications and fusions. ARQ 087 is currently being studied in a phase 1/2 clinical trial that includes a sub cohort for intrahepatic cholangiocarcinoma patients with confirmed FGFR2 gene fusions (NCT01752920).
Insights
ARQ 087 effectively inhibits cancer cell growth driven by Fibroblast Growth Factor Receptor (FGFR) dysregulation. This novel multi-kinase inhibitor shows potent anti-cancer activity in preclinical models and is under investigation in clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Dysregulation of Fibroblast Growth Factor Receptor (FGFR) signaling is implicated in various cancers.
- FGFR alterations include amplifications, mutations, and gene fusions.
Purpose of the Study:
- To evaluate the efficacy of ARQ 087, a novel small molecule multi-kinase inhibitor, against FGFR-driven cancers.
- To assess the in vitro and in vivo activity of ARQ 087 in preclinical cancer models.
Main Methods:
- Biochemical assays to determine IC50 values against FGFR1, FGFR2, and FGFR3.
- Cell-based assays measuring FGFR auto-phosphorylation, downstream signaling inhibition, cell proliferation, and cell cycle arrest.
- In vivo studies using xenograft tumor models with FGFR2 alterations.
Main Results:
- ARQ 087 demonstrated potent inhibition of FGFR kinases (IC50s in nM range).
- The compound inhibited FGFR signaling pathways, suppressed proliferation, and induced G1 cell cycle arrest and apoptosis in cancer cells.
- ARQ 087 significantly inhibited tumor growth in vivo in FGFR2-altered xenograft models.
Conclusions:
- ARQ 087 is a potent inhibitor of FGFR signaling with significant anti-cancer activity in preclinical models.
- ARQ 087 shows promise for treating cancers with FGFR dysregulation.
- A Phase 1/2 clinical trial is evaluating ARQ 087 in patients with intrahepatic cholangiocarcinoma and FGFR2 gene fusions.
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