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...

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Published in:	Cancer research (Chicago, Ill.) Vol. 67; no. 13; pp. 6383 - 6391
Main Authors:	DEMO, Susan D, KIRK, Christopher J, SHENK, Kevin D, SMYTH, Mark S, SUN, Congcong M, VALLONE, Marcy K, WOO, Tina M, MOLINEAUX, Christopher J, BENNETT, Mark K, AUJAY, Monette A, BUCHHOLZ, Tonia J, DAJEE, Maya, HO, Mark N, JING JIANG, LAIDIG, Guy J, LEWIS, Evan R, PARLATI, Francesco
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-07-2007
Subjects:	Animals Antineoplastic agents Antineoplastic Agents - pharmacology Apoptosis Biological and medical sciences Boronic Acids - pharmacology Bortezomib Chymotrypsin - metabolism Chymotrypsin - pharmacology Dose-Response Relationship, Drug Humans Inhibitory Concentration 50 Male Medical sciences Mice Neoplasm Transplantation Oligopeptides - pharmacology Pharmacology. Drug treatments Proteasome Endopeptidase Complex - metabolism Pyrazines - pharmacology Rats Rats, Sprague-Dawley Tumors Antineoplastic agent Irreversible Proteasome inhibitor Biological activity
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Abstract	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.
AbstractList	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. [Cancer Res 2007; 67(13):6383-91] Abstract 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. [Cancer Res 2007;67(13):6383–91] 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.
Author	HO, Mark N LEWIS, Evan R BENNETT, Mark K SUN, Congcong M WOO, Tina M LAIDIG, Guy J AUJAY, Monette A DEMO, Susan D KIRK, Christopher J BUCHHOLZ, Tonia J VALLONE, Marcy K DAJEE, Maya SMYTH, Mark S JING JIANG SHENK, Kevin D MOLINEAUX, Christopher J PARLATI, Francesco
Author_xml	– sequence: 1 givenname: Susan D surname: DEMO fullname: DEMO, Susan D organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 2 givenname: Christopher J surname: KIRK fullname: KIRK, Christopher J organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 3 givenname: Kevin D surname: SHENK fullname: SHENK, Kevin D organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 4 givenname: Mark S surname: SMYTH fullname: SMYTH, Mark S organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 5 givenname: Congcong M surname: SUN fullname: SUN, Congcong M organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 6 givenname: Marcy K surname: VALLONE fullname: VALLONE, Marcy K organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 7 givenname: Tina M surname: WOO fullname: WOO, Tina M organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 8 givenname: Christopher J surname: MOLINEAUX fullname: MOLINEAUX, Christopher J organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 9 givenname: Mark K surname: BENNETT fullname: BENNETT, Mark K organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 10 givenname: Monette A surname: AUJAY fullname: AUJAY, Monette A organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 11 givenname: Tonia J surname: BUCHHOLZ fullname: BUCHHOLZ, Tonia J organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 12 givenname: Maya surname: DAJEE fullname: DAJEE, Maya organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 13 givenname: Mark N surname: HO fullname: HO, Mark N organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 14 surname: JING JIANG fullname: JING JIANG organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 15 givenname: Guy J surname: LAIDIG fullname: LAIDIG, Guy J organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 16 givenname: Evan R surname: LEWIS fullname: LEWIS, Evan R organization: Proteolix, Inc, South San Francisco, California, United States – sequence: 17 givenname: Francesco surname: PARLATI fullname: PARLATI, Francesco organization: Proteolix, Inc, South San Francisco, California, United States
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Snippet	Clinical studies with bortezomib have validated the proteasome as a therapeutic target for the treatment of multiple myeloma and non-Hodgkin's lymphoma.... Abstract Clinical studies with bortezomib have validated the proteasome as a therapeutic target for the treatment of multiple myeloma and non-Hodgkin's...
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SubjectTerms	Animals Antineoplastic agents Antineoplastic Agents - pharmacology Apoptosis Biological and medical sciences Boronic Acids - pharmacology Bortezomib Chymotrypsin - metabolism Chymotrypsin - pharmacology Dose-Response Relationship, Drug Humans Inhibitory Concentration 50 Male Medical sciences Mice Neoplasm Transplantation Oligopeptides - pharmacology Pharmacology. Drug treatments Proteasome Endopeptidase Complex - metabolism Pyrazines - pharmacology Rats Rats, Sprague-Dawley Tumors
Title	Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome
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