4924 , a NEDD 8-activating enzyme inhibitor , is active in diffuse large B-cell lymphoma models : rationale for treatment of NF-B – dependent lymphoma *

MLN4924 is a potent and selective small molecule NEDD8-activating enzyme (NAE) inhibitor. In most cancer cells tested, inhibition of NAE leads to induction of DNA rereplication, resulting in DNA damage and cell death. However, in preclinical models of activated B cell–like (ABC) diffuse large B-cell lymphoma (DLBCL), we show that MLN4924 induces an alternative mechanism of action. Treatment of ABC DLBCL cells with MLN4924 resulted in rapid accumulation of pI B , decrease in nuclear p65 content, reduction of nuclear factorB (NFB) transcriptional activity, and G1 arrest, ultimately resulting in apoptosis induction, events consistent with potent NFB pathway inhibition. Treatment of germinalcenter B cell–like (GCB) DLBCL cells resulted in an increase in cellular Cdt-1 and accumulation of cells in S-phase, consistent with cells undergoing DNA rereplication. In vivo administration of MLN4924 to mice bearing human xenograft tumors of ABCand GCB-DLBCL blocked NAE pathway biomarkers and resulted in complete tumor growth inhibition. In primary human tumor models of ABC-DLBCL, MLN4924 treatment resulted in NFB pathway inhibition accompanied by tumor regressions. This work describes a novel mechanism of targeted NFB pathway modulation in DLBCL and provides strong rationale for clinical development of MLN4924 against NFB– dependent lymphomas. (Blood. 2010; 116(9):1515-1523)

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