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

• Published in: Blood Vol. 106; no. 11; p. 609
• Main Authors: Kirk, Christopher J., Bennett, Mark K., Buchholz, Tonia J., Demo, Susan D., Ho, Mark N., Jiang, Jing, Laidig, Guy J., Lewis, Evan R., Shenk, Kevin D., Smyth, Mark S., Sun, Congcong M., Vallone, Marcy K., Woo, Tina M., Molineaux, Christopher J.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 16-11-2005
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V106.11.609.609

Clinical studies using the boronic acid-based proteasome inhibitor bortezomib (VelcadeTM) 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 t1/2 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.