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Therapeutic Opportunities in Eukaryotic

Jennifer Chu1 and Jerry Pelletier1,2,3

1Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada 2Department of Oncology, McGill University, Montreal, Quebec H3G 1Y6, Canada 3Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec H3G 1Y6, Canada Correspondence: [email protected]

The ability to block biological processes with selective small molecules provides advantages distinct from most other experimental approaches. These include rapid time to onset, swift reversibility, ability to probe activities in manners that cannot be accessed by genetic means, and the potential to be further developed as therapeutic agents. Small molecule inhibitors can also be used to alter expression and activity without affecting the stoichiometry of interacting partners. These tenets have been especially evident in the field of translation. Small molecule inhibitors were instrumental in enabling investigators to capture short-lived complexes and characterize specific steps of synthesis. In addition, several drugs that are the mainstay of modern antimicrobial drug therapy are potent inhibitors of prokaryotic transla- tion. Currently, there is much interest in targeting as decades of re- search have revealed that deregulated protein synthesis in cancer cells represents a targetable vulnerability. In addition to being potential therapeutics, small molecules that manipulate translation have also been shown to influence cognitive processes such as memory. In this review, we focus on small molecule modulators that target the eukaryotic translation initiation apparatus and provide an update on their potential application to the treatment of disease.

large collection of chemical probes target- streptogramins, lincosamides, oxazolindinones, Aing various steps of prokaryotic and eukary- etc.). In the last 15 years, there has been a resur- otic translation has been identified and charac- gence of interest in targeting translation driven terized over the last ∼50 years (Pestka 1977; by a number of medical needs. One is the mul- Vazquez 1979; Pelletier and Peltz 2007; Malina tidrug resistance crisis currently facing the field et al. 2012). Early efforts in this endeavor were of medical microbiology and prompting an ur- primed by the realization that prokaryotic and gent need to identify new antibiotics. Another is eukaryotic translations differ sufficiently to en- the realization that targeting the translation able selective targeting, from which emerged apparatus in parasites, such as malaria, offers some of the most effective antimicrobial thera- a broad therapeutic window (Baragaña et al. pies (aminoglycosides, tetracyclines, macrolides, 2015). A third is the recognition that translation- chloramphenicol, clindamycin, spectinomycin, al control is frequently usurped in human can-

Editors: Michael B. Mathews, Nahum Sonenberg, and John W.B. Hershey Additional Perspectives on Translation Mechanisms and Control available at www.cshperspectives.org Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a032995

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J. Chu and J. Pelletier

cers and represents a druggable vulnerability are three isoforms), leading to reduced cap- (Silvera et al. 2010; Stumpf and Ruggero 2011; dependent translation (Pause et al. 1994). The Bhat et al. 2015; Pelletier et al. 2015; Chu et al. phosphoinositide 3-kinase (PI3K)/mechanistic 2016a). Our goal in this review is t