Manier, SalomonHuynh, DaisyShen, Yu J.Zhou, JiaYusufzai, TimurSalem, Karma Z.Ebright, Richard Y.Shi, JiantaoPark, JihyeGlavey, Siobhan V.Devine, William G.Liu, Chia-JenLeleu, XavierQuesnel, BrunoRoche-Lestienne, CatherineSnyder, John K.Brown, Lauren E.Gray, NathanaelBradner, James E.Whitesell, LukePorco, John A.Ghobrial, Irene M.2018-05-112018-05-112017-05-10Salomon Manier, Daisy Huynh, Yu J Shen, Jia Zhou, Timur Yusufzai, Karma Z Salem, Richard Y Ebright, Jiantao Shi, Jihye Park, Siobhan V Glavey, William G Devine, Chia-Jen Liu, Xavier Leleu, Bruno Quesnel, Catherine Roche-Lestienne, John K Snyder, Lauren E Brown, Nathanael Gray, James Bradner, Luke Whitesell, John A Porco, Irene M Ghobrial. 2017. "Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma." Science Translational Medicine [19466234], Volume 9, Issue 389,1946-62341946-6242https://hdl.handle.net/2144/28877Published in final edited form as: Sci Transl Med. 2017 May 10; 9(389). https://doi.org/10.1126/scitranslmed.aal2668.Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates.Medical and health sciencesBiological sciencesArticle10.1126/SCITRANSLMED.AAL2668