title: Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR Dysregulation.
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).
authors.affiliation: ArQule, Inc., Burlington, MA, United States of America.
authors.forename: Terence G
authors.initials: TG
authors.lastname: Hall
authors.affiliation: ArQule, Inc., Burlington, MA, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: ArQule, Inc., Burlington, MA, United States of America.
authors.forename: Sudharshan
authors.initials: S
authors.lastname: Eathiraj
authors.affiliation: ArQule, Inc., Burlington, MA, United States of America.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Wang
authors.affiliation: ArQule, Inc., Burlington, MA, United States of America.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Savage
authors.affiliation: ArQule, Inc., Burlington, MA, United States of America.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lapierre
authors.affiliation: ArQule, Inc., Burlington, MA, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.affiliation: ArQule, Inc., Burlington, MA, United States of America.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Abbadessa
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D019556:COS Cells / Q000187:drug effects / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D005260:Female; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy; D011799:Quinazolines / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D011799:Quinazolines; D017468:Receptors, Fibroblast Growth Factor; C000621805:derazantinib