BBB seminar: Susan Demo

Susan Demo
Proteolix Inc., South San Francisco, CA, USA

Recent clinical studies have identified the proteasome as an important therapeutic target for hematologic malignances. The proteasome inhibitor, bortezomib, has been approved for the treatment of relapsed or refractory multiple myeloma and ongoing clinical trials suggests a potential benefit for the treatment of Non-Hodgkin’s lymphoma. PR-171 is a novel epoxomicin derivative that is a potent and irreversible inhibitor of the human proteasome. It inhibits the chymotrypsin-like activity of purified human 20S proteasome with a kinact/Ki of 34,000 M-1s-1 and is >300-fold selective over the other proteasome catalytic activities. PR-171 retains its potency for inhibition of the proteasome in mammalian cells displaying IC50 values <10 nM in multiple tumor cell lines. The cellular consequences of inhibition by PR-171 include accumulation of polyubiquitinated proteins, cell cycle arrest, and induction of apoptosis. Potent cytotoxic activity of PR-171 is observed across a broad panel of human tumor cell lines (IC50 range: 2-40 nM). Pulsatile exposure studies designed to mimic the anticipated drug exposure in vivo have demonstrated that cytotoxicity is dependent upon the magnitude and duration of proteasome inhibition. These studies have also shown that hematological tumor lines are most sensitive to brief PR-171 exposure, with solid tumor lines exhibiting intermediate sensitivity and non-transformed cells being the least sensitive to such treatment. PR-171 has been found to retain its cytotoxic potential on cells made resistant to bortezomib in vitro. 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. The safety of PR-171 has been assessed in rodents and monkeys using multiple dosing schedules. 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. In rats and monkeys, daily administration of PR-171 at doses that resulted in >80% inhibition of proteasome activity in whole blood and selected tissues were well tolerated. We have also demonstrated anti-tumor activity of PR-171 in several mouse models of lymphoma and solid tumors including syngeneic and human tumor xenograft models. These studies provide the validation for the clinical testing of PR-171 in the treatment of hematologic malignancies.

Host: Jim Lorens, Department of Biomedicine