Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome.
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.
Demo
Susan D
SD
Proteolix, Inc., South San Francisco, California 94080, USA.
Kirk
Christopher J
CJ
Aujay
Monette A
MA
Buchholz
Tonia J
TJ
Dajee
Maya
M
Ho
Mark N
MN
Jiang
Jing
J
Laidig
Guy J
GJ
Lewis
Evan R
ER
Parlati
Francesco
F
Shenk
Kevin D
KD
Smyth
Mark S
MS
Sun
Congcong M
CM
Vallone
Marcy K
MK
Woo
Tina M
TM
Molineaux
Christopher J
CJ
Bennett
Mark K
MK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002918:Chymotrypsin / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D001897:Boronic Acids; D009842:Oligopeptides; D011719:Pyrazines; D000069286:Bortezomib; C524865:carfilzomib; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex