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

Abstract

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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.