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Experimental and Molecular Therapeutics 48: Antiangiogenesis and Antivascular Agents

In vivo efficacy of novel methionine aminopeptidase 2 inhibitors, alone and in combination with clinical drugs and a novel Bcl-2 inhibitor

Jonathan A. Meulbroek, Jason Stavropoulos, Amanda Niquette, Yi-Chun Wang, Gail Bukofzer, Michael J. Mitten, Qian Zhang, David M. Barnes, Nwe Bamaung, Steven W. Elmore, Lora A. Garcia, Jieyi Wang, George Sheppard, Randy Bell, Saul Rosenberg, David J. Frost and Cherrie K. Donawho
Jonathan A. Meulbroek
Abbott Laboratories, Abbott Park, IL
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Jason Stavropoulos
Abbott Laboratories, Abbott Park, IL
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Amanda Niquette
Abbott Laboratories, Abbott Park, IL
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Yi-Chun Wang
Abbott Laboratories, Abbott Park, IL
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Gail Bukofzer
Abbott Laboratories, Abbott Park, IL
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Michael J. Mitten
Abbott Laboratories, Abbott Park, IL
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Qian Zhang
Abbott Laboratories, Abbott Park, IL
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David M. Barnes
Abbott Laboratories, Abbott Park, IL
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Nwe Bamaung
Abbott Laboratories, Abbott Park, IL
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Steven W. Elmore
Abbott Laboratories, Abbott Park, IL
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Lora A. Garcia
Abbott Laboratories, Abbott Park, IL
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Jieyi Wang
Abbott Laboratories, Abbott Park, IL
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George Sheppard
Abbott Laboratories, Abbott Park, IL
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Randy Bell
Abbott Laboratories, Abbott Park, IL
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Saul Rosenberg
Abbott Laboratories, Abbott Park, IL
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David J. Frost
Abbott Laboratories, Abbott Park, IL
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Cherrie K. Donawho
Abbott Laboratories, Abbott Park, IL
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DOI:  Published May 2005
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Proc Amer Assoc Cancer Res, Volume 46, 2005

Abstract

5840

Compounds with nanomolar potency against human Methionine aminopeptidase-2 (MetAP2), an intracellular enzyme responsible for the removal of the N-terminal initiator methionine from nascent proteins, were tested in a number of different models. In the mouse cornea angiogenesis model, the new compounds had similar activity to TNP-470, an irreversible inhibitor of MetAP2 originally promoted for its antiangiogenic activity, with >25% inhibition of VEGF- and bFGF-induced angiogenesis. In a B16F10 SC flank screening model, several compounds, including A-800141 (MetAP2 IC50 = 0.017 μM), had activity similar to TNP-470, and were selected for further evaluation. Models of colon carcinomas and of B cell lymphomas were chosen because of their relatively high expression of MetAP2 as tested by IHC. Dosing with A-800141, a molecule with improved PK A-849519 (MetAP2 IC50 = 0.017 μM) and standard clinical drugs was initiated either 1 day after tumor cell injection (early treatment model) or at a predetermined mean tumor volume of the study group (size match model). Against the HCT-116 colon carcinoma (early treatment model), A-800141 dosing (150 mg/kg/day, PO, BID) resulted in T/C of 34% (day 20), based on mean tumor volumes, while irinotecan dosing resulted in T/C of 5% (day 20, 12.5 mg/kg/day, IP, Q3D x 4). Furthermore, simultaneous dosing of A-800141 and irinotecan resulted in prolonged tumor growth delay if A-800141 dosing continued, demonstrating superiority of the combination over irinotecan alone. Against the DLD-1 colon carcinoma (size match model), A-800141 dosing (as above) resulted in T/C of 63% (day 28), while irinotecan dosing resulted in T/C of 35% (day 28, 10 mg/kg/day, IP, QD), suggesting it is a more difficult to treat tumor (as compared to HCT-116). Against the SuDHL4 B cell lymphoma (size match model), A-800141 dosing (as above) resulted in T/C of 85% while etoposide dosing (15 mg/kg/day, IP, Q4D x 3) resulted in T/C of 99% (both day 18). In combination therapy, A-800141 plus etoposide resulted in T/C of 42% (day 18) when dosed simultaneously. Against the DoHH-2 B cell lymphoma (size match model), which bears the t(14;18) translocation resulting overexpression of Bcl-2, a simultaneous combination of A-849519 plus ABT-737, a potent inhibitor of Bcl-2 also in preclinical development, was evaluated. A-849519 dosing (150 mg/kg/day, PO, BID) plus ABT-737 dosing (75 mg/kg/day, IP, QD) resulted in T/C of 24%, while A-800141 and ABT-737 monotherapies resulted in T/Cs of 58% and 45%, respectively (all day 27). These results demonstrate the activity of the newly discovered oral compounds for MetAP2 targeted therapy.

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Cancer Research: 65 (9 Supplement)
May 2005
Volume 65, Issue 9 Supplement
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In vivo efficacy of novel methionine aminopeptidase 2 inhibitors, alone and in combination with clinical drugs and a novel Bcl-2 inhibitor
Jonathan A. Meulbroek, Jason Stavropoulos, Amanda Niquette, Yi-Chun Wang, Gail Bukofzer, Michael J. Mitten, Qian Zhang, David M. Barnes, Nwe Bamaung, Steven W. Elmore, Lora A. Garcia, Jieyi Wang, George Sheppard, Randy Bell, Saul Rosenberg, David J. Frost and Cherrie K. Donawho
Cancer Res May 1 2005 (65) (9 Supplement) 1374;

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In vivo efficacy of novel methionine aminopeptidase 2 inhibitors, alone and in combination with clinical drugs and a novel Bcl-2 inhibitor
Jonathan A. Meulbroek, Jason Stavropoulos, Amanda Niquette, Yi-Chun Wang, Gail Bukofzer, Michael J. Mitten, Qian Zhang, David M. Barnes, Nwe Bamaung, Steven W. Elmore, Lora A. Garcia, Jieyi Wang, George Sheppard, Randy Bell, Saul Rosenberg, David J. Frost and Cherrie K. Donawho
Cancer Res May 1 2005 (65) (9 Supplement) 1374;
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Show more Experimental and Molecular Therapeutics 48: Antiangiogenesis and Antivascular Agents
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