Pharmacokinetics, Pharmacodynamics and Anti-Tumor Efficacy of PR-171, a Novel Inhibitor of the 20S Proteasome.

Clinical studies using the boronic acid-based proteasome inhibitor bortezomib (Velcade^TM) have validated the proteasome as a therapeutic intervention point for the treatment of multiple myeloma and non-Hodgkin’s Lymphoma. Despite encouraging clinical response rates with this drug, significant toxicities, including neutropenia, thrombocytopenia and peripheral neuropathy have restricted the intensity of bortezomib dosing. PR-171 is a novel peptide epoxyketone inhibitor that selectively and irreversibly inhibits the chymotryptic subunit of the 20S proteasome. We have characterized the pharmacokinetics, pharmacodynamics and anti-tumor efficacy of PR-171 in rodents and non-human primates. PR-171 is rapidly cleared from the plasma compartment following intravenous bolus administration, with a terminal half-life in rats and monkeys of 15 and 7.2 min, respectively. Despite this rapid clearance, PR-171 administration results in a prolonged dose-dependent inhibition of the 20S proteasome in all tissues examined with the exception of brain. Single doses of PR-171 that are tolerated in mice, rats and monkeys result in greater than 90% inhibition of proteasome activity in blood and many tissues. Recovery of proteasome activity following exposure to PR-171 is dependent upon synthesis of new proteasome subunits and occurs with a t_1/2 of ~ 24 hr in nucleated cells. Recovery of proteasome activity in erythrocytes is dependent upon red blood cell turnover and occurs more slowly in animals. The safety of PR-171 has been assessed in rodents using multiple dosing schedules including weekly, biweekly, daily and BID administration. In rats, daily administration of PR-171 at doses that resulted in >80% inhibition of proteasome activity in whole blood and selected tissues were well tolerated. Recovery of proteasome activity following repeated daily administrations was unchanged from that seen after a single dose. PR-171 was also well tolerated when administered daily to monkeys at equivalent doses on a body surface area comparison. A transient thrombocytopenia was noted in both rats and monkeys but neutrophil and lymphocyte counts were not decreased in response to PR-171 administration. PR-171 induced a significant anti-tumor response in beige-nu-xid (BNX) triple immunodeficient mice bearing established HS-Sultan Burkitt’s lymphoma tumors and in Balb/c mice challenged with A20 lymphoma cells. We have also demonstrated anti-tumor activity of PR-171 in several mouse models of solid tumors including syngeneic and human tumor xenograft models of colorectal cancer. These studies demonstrate the tolerability, anti-tumor activity and dosing flexibility of PR-171 and provide validation for the clinical testing of PR-171 in the treatment of hematologic malignancies utilizing dose intensive schedules.