Fv-162 Is A Novel Orally Bioavailable Proteasome Inhibitor With Improved Pharmacokinetics That Displays Preclinical Efficacy In Vitro And In Vivo

Proteasome inhibitors (PIs), such as bortezomib and carfilzomib, are often associated with serious toxicities, poor pharmacokinetics (PK), and the inconvenience of intravenous administration. Therefore, there is a need for safer and more effective orally active PIs. Applying a novel fluorine-based medicinal chemistry technology, we designed, synthesized and tested novel proprietary analogs of epoxyketone-based PIs. Our initial screening identified a lead orally bioavailable PI, FV-162, which had superior potency in proteasome activity inhibition, cytotoxicity in cultured human multiple myeloma (MM) cells and metabolic stability in mouse liver microsomes, compared to an oral PI currently under clinical evaluation, ONX-0912.