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.

Development of a Potent Inhibitor of the Plasmodium Proteasome with Reduced Mammalian Toxicity

“…In addition, two orally bioavailable epoxyketone inhibitors have been developed that have potent antimyeloma activity. 35 , 36 One of these inhibitors, oprozomib (ONX 0912), 35 is in phase 1 clinical trial. These anticancer drug studies will provide the framework for design of antiplasmodial proteasome inhibitors with good pharmacokinetic and pharmacodynamic properties.…”

“…An oral proteasome inhibitor has been approved for treatment of multiple myeloma that consists of a prodrug that is released under aqueous conditions into a peptide boronic acid proteasome inhibitor. In addition, two orally bioavailable epoxyketone inhibitors have been developed that have potent antimyeloma activity. , One of these inhibitors, oprozomib (ONX 0912), is in phase 1 clinical trial. These anticancer drug studies will provide the framework for design of antiplasmodial proteasome inhibitors with good pharmacokinetic and pharmacodynamic properties.…”