Clinical studies with
bortezomib have validated the
proteasome as a therapeutic target for the treatment of
multiple myeloma and
non-Hodgkin's lymphoma. However, significant toxicities have restricted the intensity of
bortezomib dosing. Here we describe the antitumor activity of
PR-171, a novel epoxyketone-based irreversible
proteasome inhibitor that is currently in clinical development. In comparison to
bortezomib,
PR-171 exhibits equal potency but greater selectivity for the
chymotrypsin-like activity of the
proteasome. In cell culture,
PR-171 is more cytotoxic than
bortezomib following brief treatments that mimic the in vivo pharmacokinetics of both molecules. Hematologic
tumor cells exhibit the greatest sensitivity to brief exposure, whereas solid
tumor cells and nontransformed cell types are less sensitive to such treatments. Cellular consequences of
PR-171 treatment include the accumulation of
proteasome substrates and induction of cell cycle arrest and/or apoptosis. Administration of
PR-171 to animals results in the dose-dependent inhibition of the
chymotrypsin-like
proteasome activity in all tissues examined with the exception of the brain.
PR-171 is well tolerated when administered for either 2 or 5 consecutive days at doses resulting in >80%
proteasome inhibition in blood and most tissues. In human
tumor xenograft models,
PR-171 mediates an antitumor response that is both dose and schedule dependent. The antitumor efficacy of
PR-171 delivered on 2 consecutive days is stronger than that of
bortezomib administered on its clinical dosing schedule. These studies show the tolerability, efficacy, and dosing flexibility of
PR-171 and provide validation for the clinical testing of
PR-171 in the treatment of
hematologic malignancies using dose-intensive schedules.