title: FV-162 is a novel, orally bioavailable, irreversible proteasome inhibitor with improved pharmacokinetics displaying preclinical efficacy with continuous daily dosing.
abstract: Approved proteasome inhibitors have advanced the treatment of multiple myeloma but are associated with serious toxicities, poor pharmacokinetics, and most with the inconvenience of intravenous administration. We therefore sought to identify novel orally bioavailable proteasome inhibitors with a continuous daily dosing schedule and improved therapeutic window using a unique drug discovery platform. We employed a fluorine-based medicinal chemistry technology to synthesize 14 novel analogs of epoxyketone-based proteasome inhibitors and screened them for their stability, ability to inhibit the chymotrypsin-like proteasome, and antimyeloma activity in vitro. The tolerability, pharmacokinetics, pharmacodynamic activity, and antimyeloma efficacy of our lead candidate were examined in NOD/SCID mice. We identified a tripeptide epoxyketone, FV-162, as a metabolically stable, potent proteasome inhibitor cytotoxic to human myeloma cell lines and primary myeloma cells. FV-162 had limited toxicity and was well tolerated on a continuous daily dosing schedule. Compared with the benchmark oral irreversible proteasome inhibitor, ONX-0192, FV-162 had a lower peak plasma concentration and longer half-life, resulting in a larger area under the curve (AUC). Oral FV-162 treatment induced rapid, irreversible inhibition of chymotrypsin-like proteasome activity in murine red blood cells and inhibited tumor growth in a myeloma xenograft model. Our data suggest that oral FV-162 with continuous daily dosing schedule displays a favorable safety, efficacy, and pharmacokinetic profile in vivo, identifying it as a promising lead for clinical evaluation in myeloma therapy.
authors.affiliation: 1] Princess Margaret Cancer Centre, Toronto, ON, Canada [2] Fluorinov Pharma Inc., Toronto, ON, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Fluorinov Pharma Inc., Toronto, ON, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Dove
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Shamas-Din
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Nachman
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Oh
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Hurren
authors.affiliation: Department of Molecular Genetics, Biochemistry and Chemistry, University of Toronto, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Ruschak
authors.affiliation: Fluorinov Pharma Inc., Toronto, ON, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Climie
authors.affiliation: Ontario Institute for Cancer Research, Toronto, ON, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Press
authors.affiliation: Ontario Institute for Cancer Research, Toronto, ON, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Griffin
authors.affiliation: Ontario Institute for Cancer Research, Toronto, ON, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Undzys
authors.affiliation: Ontario Institute for Cancer Research, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Aman
authors.affiliation: Ontario Institute for Cancer Research, Toronto, ON, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Al-awar
authors.affiliation: Department of Molecular Genetics, Biochemistry and Chemistry, University of Toronto, Toronto, ON, Canada.
authors.forename: L E
authors.initials: LE
authors.lastname: Kay
authors.affiliation: 1] Fluorinov Pharma Inc., Toronto, ON, Canada [2] Ontario Institute for Cancer Research, Toronto, ON, Canada.
authors.forename: D
authors.initials: D
authors.lastname: O'Neill
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Trudel
authors.affiliation: Fluorinov Pharma Inc., Toronto, ON, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Slassi
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: A D
authors.initials: AD
authors.lastname: Schimmer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005461:Fluorine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000008:administration & dosage*; D061988:Proteasome Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000607362:FV-162; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D005461:Fluorine