Abstract 3075: Antitumor activity of M8891, a potent and reversible inhibitor of methionine aminopeptidase 2

Abstract

N-terminal cleavage of methionine by methionine aminopeptidases is a crucial step in the maturation of proteins during protein biosynthesis. MetAP2, one of the two methionine aminopeptidases expressed in mammalian cells, has been identified as the target of the highly potent and irreversible inhibitor fumagillin to which antiangiogenic and antitumoral properties have been ascribed. This and other findings support the rationale to develop MetAP2 inhibitors for cancer therapy. The fumagillin derivative TNP-470 has been evaluated in several clinical trials, but development was discontinued following demonstration of unfavorable pharmacokinetics and side effects likely attributed to the reactivity of the compound. We have developed M8891, an orally bioavailable, potent, and reversible inhibitor of MetAP2. M8891 inhibited growth of primary endothelial cells as well as patient-derived tumor cells and demonstrated antiangiogenic and antitumoral activity in mouse models. Accumulation of an unprocessed MetAP2 substrate, methionylated elongation factor 1 α, Met-EF1a, was observed upon treatment with M8891 in vitro as well as in vivo confirming that MetAP2 can be effectively inhibited with this compound. In combination with sunitinib, M8891 demonstrated strong and durable antitumor activity in a cohort of patient-derived renal cancer xenografts at well-tolerated exposure levels. Predictive biomarker hypotheses generated from CRISPR sensitivity/resistance screens as well as analyses of molecular profiling data from PDX tumors are currently being evaluated in further nonclinical studies. A dose-escalation phase 1 study in patients with advanced solid tumors is currently ongoing. Citation Format: Manja Friese-Hamim, Olga Bogatyrova, Maria J. Ortiz, Dirk Wienke, Timo Heinrich, Felix Rohdich, Klaus Duecker, Christoph Schultes, Bayard Huck, Frank T. Zenke, Andree Blaukat. Antitumor activity of M8891, a potent and reversible inhibitor of methionine aminopeptidase 2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3075.