Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription

Struntz, Nicholas B.; Chen, Andrew I; Deutzmann, Anja; Wilson, Robert M.; Stefan, Eric; Evans, Helen L.; Ramirez, Maricela; Liang, Tong; Caballero, Francisco; Wildschut, Mattheus H.E.; Neel, Dylan V.; Freeman, David B.; Pop, Marius; McConkey, Marie; Muller, Sandrine; Curtin, Brice H.; Tseng, Hanna; Frombach, Kristen R.; Butty, Vincent; Levine, Stuart S.; Féau, Clémentine; Elmiligy, Sarah; Hong, Jiyoung A.; Lewis, Timothy A.; Vetere, Amedeo; Clemons, Paul A.; Malstrom, Scott; Ebert, Benjamin L.; Lin, Charles Y.; Felsher, Dean W.; Koehler, Angela N.

doi:10.1016/j.chembiol.2019.02.009

Cited by 101 publications

(66 citation statements)

References 68 publications

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“…This is consistent with a recent study showing the same effect on MYC stability (Supplemental Fig. S7F-H; Struntz et al 2019). In addition, induction of Omomyc, a peptide that binds to MYC's bHLH region, also led to decreased MYC protein levels, suggesting that the effect on MYC stability is not due to a lack of binding at its dimerization interface ( Fig.…”

Section: Max Loss or Inhibition Of Myc-max Dimerization Results In Resupporting

confidence: 94%

Maxdeletion destabilizes MYC protein and abrogates Eµ-Myclymphomagenesis

et al. 2019

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Although MAX is regarded as an obligate dimerization partner for MYC, its function in normal development and neoplasia is poorly defined. We show that B-cell-specific deletion of Max has a modest effect on B-cell development but completely abrogates Eµ-Myc-driven lymphomagenesis. While Max loss affects only a few hundred genes in normal B cells, it leads to the global down-regulation of Myc-activated genes in premalignant Eµ-Myc cells. We show that the balance between MYC-MAX and MNT-MAX interactions in B cells shifts in premalignant B cells toward a MYC-driven transcriptional program. Moreover, we found that MAX loss leads to a significant reduction in MYC protein levels and down-regulation of direct transcriptional targets, including regulators of MYC stability. This phenomenon is also observed in multiple cell lines treated with MYC-MAX dimerization inhibitors. Our work uncovers a layer of Myc autoregulation critical for lymphomagenesis yet partly dispensable for normal development.

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Section: Max Loss or Inhibition Of Myc-max Dimerization Results In Resupporting

confidence: 94%

Maxdeletion destabilizes MYC protein and abrogates Eµ-Myclymphomagenesis

et al. 2019

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“…However, MYCMI-6 does not lead to MYC protein degradation, and, therefore, the MAX-independent functions of MYC will need to be well-understood in this therapeutic setting[97]. Alternatively, Struntz et al[98] demonstrate that stabilization of MAX:MAX homodimers, using the small molecule KI-MS2-008, leads to MYC…”

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confidence: 99%

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Allen-Petersen¹,

Sears²

2019

BioDrugs

134

110

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MYC is a master transcriptional regulator that controls almost all cellular processes. Over the last several decades, researchers have strived to define the context-dependent transcriptional gene programs that are controlled by MYC, as well as the mechanisms that regulate MYC function, in an effort to better understand the contribution of this oncoprotein to cancer progression. There are a wealth of data indicating that deregulation of MYC activity occurs in a large number of cancers and significantly contributes to disease progression, metastatic potential, and therapeutic resistance. Although the therapeutic targeting of MYC in cancer is highly desirable, there remain substantial structural and functional challenges that have impeded direct MYC-targeted drug development and efficacy. While efforts to drug the 'undruggable' may seem futile given these challenges and considering the broad reach of MYC, significant strides have been made to identify points of regulation that can be exploited for therapeutic purposes. These include targeting the deregulation of MYC transcription in cancer through small-molecule inhibitors that induce epigenetic silencing or that regulate the G-quadruplex structures within the MYC promoter. Alternatively, compounds that disrupt the DNA-binding activities of MYC have been the long-standing focus of many research groups, since this method would prevent downstream MYC oncogenic activities regardless of upstream alterations. Finally, proteins involved in the post-translational regulation of MYC have been identified as important surrogate targets to reduce MYC activity downstream of aberrant cell stimulatory signals. Given the complex regulation of the MYC signaling pathway, a combination of these approaches may provide the most durable response, but this has yet to be shown. Here, we provide a comprehensive overview of the different therapeutic strategies being employed to target oncogenic MYC function, with a focus on post-translational mechanisms.

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“…Inhibition of Myc activation has been attempted by several different modalities . Small molecules that disrupt Myc/Max heterodimerization have been ineffective .…”

Section: Discussionmentioning

confidence: 99%

“…One such protein is ME47, which is a hybrid protein with Max's DNA binding domain fused onto the dimerization domain of E47, which inhibits Myc by blocking Myc/Max binding to E‐boxes in promoters of Myc‐regulated genes . Recently, KI‐MS2‐008 has been described as a compound that binds to Max and promotes Max homodimerization to inhibit Myc transcriptional activation . An alternative mode of inhibition is the stabilization of Mxd1 by inhibiting Myc‐mediated activation, a small molecule inhibitor of cIAP1, referred to as D‐19, has been shown to stabilize Mxd1 levels in cells, while reducing the overall Myc levels in cells .…”

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confidence: 99%

Inhibition of Myc transcriptional activity by a mini‐protein based upon Mxd1

et al. 2020

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Myc, a transcription factor with oncogenic activity, is upregulated by amplification, translocation, and mutation of the cellular pathways that regulate its stability. Inhibition of the Myc oncogene by various modalities has had limited success. One Myc inhibitor, Omomyc, has limited cellular and in vivo activity. Here, we report a mini‐protein, referred to as Mad, which is derived from the cellular Myc antagonist Mxd1. Mad localizes to the nucleus in cells and is 10‐fold more potent than Omomyc in inhibiting Myc‐driven cell proliferation. Similar to Mxd1, Mad also interacts with Max, the binding partner of Myc, and with the nucleolar upstream binding factor. Mad binds to E‐Box DNA in the promoters of Myc target genes and represses Myc‐mediated transcription to a greater extent than Omomyc. Overall, Mad appears to be more potent than Omomyc both in vitro and in cells.

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Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription

Cited by 101 publications

References 68 publications

Maxdeletion destabilizes MYC protein and abrogates Eµ-Myclymphomagenesis

Maxdeletion destabilizes MYC protein and abrogates Eµ-Myclymphomagenesis

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Inhibition of Myc transcriptional activity by a mini‐protein based upon Mxd1

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