Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models.

Autor:	Friese-Hamim M; Research Unit Oncology, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany., Ortiz Ruiz MJ; Research Unit Oncology, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany., Bogatyrova O; Research Unit Oncology, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany., Keil M; Research Unit Oncology, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany., Rohdich F; Discovery Technologies, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany., Blume B; Discovery Technologies, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany., Leuthner B; Discovery Technologies, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany., Czauderna F; Research Unit Oncology, EMD Serono Research & Development Institute Inc., Billerica, Massachusetts., Hahn D; Research Unit Oncology, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany., Jabs J; Research Unit Oncology, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany., Jaehrling F; Research Unit Oncology, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany., Heinrich T; Discovery Technologies, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany., Kellner R; Discovery Technologies, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany., Chan K; Donnelly Centre, University of Toronto, Toronto, Ontario, Canada., Tong AHY; Donnelly Centre, University of Toronto, Toronto, Ontario, Canada., Wienke D; Research Unit Oncology, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany., Moffat J; Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.; Institute for Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada., Blaukat A; Research Unit Oncology, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany., Zenke FT; Research Unit Oncology, Merck Healthcare KGaA, the healthcare business of Merck KGaA, Darmstadt, Germany.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2024 Feb 01; Vol. 23 (2), pp. 159-173.
DOI:	10.1158/1535-7163.MCT-23-0102
Abstrakt:	N-terminal processing by methionine aminopeptidases (MetAP) is a crucial step in the maturation of proteins during protein biosynthesis. Small-molecule inhibitors of MetAP2 have antiangiogenic and antitumoral activity. Herein, we characterize the structurally novel MetAP2 inhibitor M8891. M8891 is a potent, selective, reversible small-molecule inhibitor blocking the growth of human endothelial cells and differentially inhibiting cancer cell growth. A CRISPR genome-wide screen identified the tumor suppressor p53 and MetAP1/MetAP2 as determinants of resistance and sensitivity to pharmacologic MetAP2 inhibition. A newly identified substrate of MetAP2, translation elongation factor 1-alpha-1 (EF1a-1), served as a pharmacodynamic biomarker to follow target inhibition in cell and mouse studies. Robust angiogenesis and tumor growth inhibition was observed with M8891 monotherapy. In combination with VEGF receptor inhibitors, tumor stasis and regression occurred in patient-derived xenograft renal cell carcinoma models, particularly those that were p53 wild-type, had Von Hippel-Landau gene (VHL) loss-of-function mutations, and a mid/high MetAP1/2 expression score. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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