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Review
. 2015 May;1849(5):525-43.
doi: 10.1016/j.bbagrm.2014.03.005. Epub 2014 Mar 19.

Small-molecule inhibitors of the Myc oncoprotein

Steven Fletcher  1 , Edward V Prochownik  2
Affiliations
Review

Small-molecule inhibitors of the Myc oncoprotein

Steven Fletcher et al. Biochim Biophys Acta. 2015 May.

Abstract

The c-Myc (Myc) oncoprotein is among the most attractive of cancer targets given that it is de-regulated in the majority of tumors and that its inhibition profoundly affects their growth and/or survival. However, its role as a seldom-mutated transcription factor, its lack of enzymatic activity for which suitable pharmaceutical inhibitors could be crafted and its expression by normal cells have largely been responsible for its being viewed as "undruggable". Work over the past several years, however, has begun to reverse this idea by allowing us to view Myc within the larger context of global gene regulatory control. Thus, Myc and its obligate heterodimeric partner, Max, are integral to the coordinated recruitment and post-translational modification of components of the core transcriptional machinery. Moreover, Myc over-expression re-programs numerous critical cellular functions and alters the cell's susceptibility to their inhibition. This new knowledge has therefore served as a framework upon which to develop new pharmaceutical approaches. These include the continuing development of small molecules which act directly to inhibit the critical Myc-Max interaction, those which act indirectly to prevent Myc-directed post-translational modifications necessary to initiate productive transcription and those which inhibit vital pathways upon which the Myc-transformed cell is particularly reliant. This article is part of a Special Issue entitled: Myc proteins in cell biology and pathology.

Keywords: Cancer; Max; Myc; Protein–protein interaction; Small-molecule inhibitor; Transcription factor.

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Figures

Fig. 1
Fig. 1
Structures of IIA6B17 and IIA4B20 (129) and their analogs mycmycin-1 and mycmycin-2 (132).
Fig. 2
Fig. 2
Structure of NZY2267 (see ref. 133)
Fig. 3
Fig. 3
Structures of Mycro1 and Mycro2.
Fig. 4
Fig. 4
Structures of 10058-F4 and 10074-G5
Fig. 5
Fig. 5
Structures of JY-3-094 and SF-4-017.
Fig. 6
Fig. 6
Kyte-Doolittle hydrophobicity plots for residues 400–415 of Myc and the corresponding residues of N-Myc and L-Myc that are the presumptive sites for 10058-F4 binding. A window setting of 7 was used for all three plots (http://web.expasy.org/protscale/). Note that proteins have regions of comparable hydropbobicity that lie at the N-terminus of the core 10058-F4 binding site and that are associated with abrupt hydrophilic transitions.
Fig. 7
Fig. 7
Kyte-Doolittle plots for Myc binding sites for 10074-G5 (residues 359–375) and 10074-A4 (residues 373–386) (140,142). All settings were identical to those described in Fig. 6. Note the abrupt transitions from relatively hydrophobic sites to hydrophilic sites in both cases.
Fig. 8
Fig. 8
Structures of BET domain inhibitors
Fig. 9
Fig. 9
Structures of MYRA-A and MYRA-B
Fig. 10
Fig. 10
Summary of the distinct points of action and mechanisms of action of small molecule Myc inhibitors. Bold lettering depicts the time- and context-dependent changes in Myc and its downstream targets and function. Thus, the initial synthesis of Myc is followed by its heterodimerization with Max, its binding to chromatin and its association with and regulation of the transcriptional machinery to relive RNA PolII pausing. Deregulated transcription leads to the phenotypic changes that are characteristic of Myc-specific transformation, including aberrant DNA synthesis and the promotion of genomic instability. Green boxes indicate points where synthetic lethal interactions have been identified. Representative pharmacologic agents from each of the different categories of Myc inhibitors are depicted in red. The dotted arrow indicates that transcription of the MYCC gene itself is BRD4-dependent. Also note that synthetic lethal interactions can occur as a result of either increasing or decreasing Myc protein levels. In the first case, this is achieved by inhibiting GSK3β with compounds such as 6-bromoindirubin-3-oxime (6B3O). Increased Myc levels then render cells more sensitive to certain agents such as DR5 agonists. Myc degradation is promoted by agents such as artemisinin and its analogs. Although these increase Myc Thr58 phosphorylation, it is not clear if this is accomplished by a direct stiulation of GSK3β. See text for details as to the mechanism of action of specific inhibitors.
Fig. 11
Fig. 11
Structure of the Max–Max homodimer stabilizer NSC13728.
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