Preclinical evaluation of MLN4924, the first small molecule inhibitor of NEDD8-activating enzyme (NAE) for the treatment of cancer
MOLECULAR CANCER THERAPEUTICS(2007)
Abstract
B280 Nedd8-Activating Enzyme (NAE) initiates the conjugation of the ubiquitin-like protein nedd8 to its cellular targets, members of the cullin protein family. Nedd8 conjugation to cullins is known to be essential for the ubiquitination activity of cullin-dependent ubiquitin ligases (CDLs). These CDLs control the timely ubiquitination and subsequent degradation of many proteins with important roles in cell cycle progression and signal transduction. These cellular processes are relevant to tumor growth and survival providing a rationale for inhibiting NAE as an anti-cancer strategy. Targeting NAE for the therapeutic intervention of human cancers is unprecedented. Here we describe MLN4924, the first small molecule inhibitor of NAE. MLN4924 potently inhibits the growth of a variety of human tumor-derived cell lines in vitro and growth inhibition correlates with NAE inhibition. We demonstrate that MLN4924 inhibits the nedd8 conjugation pathway in cells, resulting in stabilization of numerous CDL substrates and disruption of protein homeostasis. In most of the cell lines studied, the mechanism of cell growth inhibition appears to be a consequence of uncontrolled DNA synthesis in the S-phase of the cell cycle followed by induction of a DNA damage response and apoptosis. This phenotype is consistent with DNA re-replication. In vivo administration of a single dose of MLN4924 to mice harboring human subcutaneous HCT-116 and Calu-6 xenografts results in a pharmacodynamic response of nedd8-pathway inhibition in the tumor. MLN4924 results in time and dose-dependent inhibition of the formation of total neddylated cullins and stabilization of CDL substrates as illustrated by the increased levels of the CDL3Keap1 substrate, Nrf-2. Inhibition of the nedd8 pathway in these tumors following repeated daily or intermittent dosing of MLN4924 translates into significant tumor growth inhibition at doses that are well tolerated. MLN4924 is the first small molecule inhibitor of NAE with a demonstrated pharmacodynamic response and anti-tumor activity and is expected to enter Phase I clinical trials in 2008.
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Key words
first small molecule inhibitor,mln4924,enzyme
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