Small molecule inhibitors of Myc/Max dimerization and Myc-induced cell transformation

Jin, Shi; Stover, James S.; Whitby, Landon R.; Vogt, Peter K.; Boger, Dale L.

doi:10.1016/j.bmcl.2009.09.044

Cited by 49 publications

(37 citation statements)

References 49 publications

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“…Several groups, including our own, have identified small-molecule inhibitors that target c-Myc protein-protein complexes and thereby inhibit the growth of c-Myc-dependent cell lines in vitro (Yin et al, 2003;Kiessling et al, 2006;Berg, 2008;Shi et al, 2009). These studies provide evidence that bHLH-ZIP proteins are druggable targets, although translating these in vitro observations into antitumor activity in animals has been met with limited success (Guo et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Because c-Myc must heterodimerize with its obligatory bHLH-ZIP partner Max to exhibit transcriptional activity (Walhout et al, 1997), several groups have designed smallmolecule inhibitors to interfere with this protein-protein dimerization and thereby inactivate c-Myc function (Berg et al, 2002;Yin et al, 2003;Kiessling et al, 2006;Xu et al, 2006;Wang et al, 2007;Hammoudeh et al, 2009;Shi et al, 2009). Berg et al (2002) showed that small molecules can interfere with c-Myc/Max dimerization and inhibit c-Mycdependent transformation of chicken embryo fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Cytotoxicity and In Vivo Efficacy, Pharmacokinetics, and Metabolism of 10074-G5, a Novel Small-Molecule Inhibitor of c-Myc/Max Dimerization

Clausen

Guo²,

Parise³

et al. 2010

J Pharmacol Exp Ther

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The c-Myc oncoprotein is overexpressed in many tumors and is essential for maintaining the proliferation of transformed cells. To function as a transcription factor, c-Myc must dimerize with Max via the basic helix-loop-helix leucine zipper protein (bHLH-ZIP) domains in each protein. The small molecule 7-nitro-N-(2-phenylphenyl)-2,1,3-benzoxadiazol-4-amine (10074-G5) binds to and distorts the bHLH-ZIP domain of c-Myc, thereby inhibiting c-Myc/Max heterodimer formation and inhibiting its transcriptional activity. We report in vitro cytotoxicity and in vivo efficacy, pharmacodynamics, pharmacokinetics, and metabolism of 10074-G5 in human xenograft-bearing mice. In vitro, 10074-G5 inhibited the growth of Daudi Burkitt's lymphoma cells and disrupted c-Myc/Max dimerization. 10074-G5 had no effect on the growth of Daudi xenografts in C.B-17 SCID mice that were treated with 20 mg/kg 10074-G5 intravenously for 5 consecutive days. Inhibition of c-Myc/Max dimerization in Daudi xenografts was not seen 2 or 24 h after treatment. Concentrations of 10074-G5 in various matrices were determined by high-performance liquid chromatography-UV, and metabolites of 10074-G5 were identified by liquid chromatography/tandem mass spectrometry. The plasma half-life of 10074-G5 in mice treated with 20 mg/kg i.v. was 37 min, and peak plasma concentration was 58 M, which was 10-fold higher than peak tumor concentration. The lack of antitumor activity probably was caused by the rapid metabolism of 10074-G5 to inactive metabolites, resulting in tumor concentrations of 10074-G5 insufficient to inhibit c-Myc/Max dimerization. Our identification of 10074-G5 metabolites in mice will help design new, more metabolically stable small-molecule inhibitors of c-Myc.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Vitro Cytotoxicity and In Vivo Efficacy, Pharmacokinetics, and Metabolism of 10074-G5, a Novel Small-Molecule Inhibitor of c-Myc/Max Dimerization

Clausen

Guo²,

Parise³

et al. 2010

J Pharmacol Exp Ther

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“…For example, compounds have been identified that disrupt the interaction between MYC and its transcriptional partner MAX to suppress downstream gene transcription (20)(21)(22)(23)(24). In addition, molecules have been developed that stabilize the DNA G-quadruplex secondary structure in the MYC promoter region to down-regulate its own transcription (25, 26).…”

mentioning

confidence: 99%

Small molecule selectively suppresses MYC transcription in cancer cells

Bouvard

Lim

Ludka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Stauprimide is a staurosporine analog that promotes embryonic stem cell (ESC) differentiation by inhibiting nuclear localization of the MYC transcription factor NME2, which in turn results in downregulation of MYC transcription. Given the critical role the oncogene MYC plays in tumor initiation and maintenance, we explored the potential of stauprimide as an anticancer agent. Here we report that stauprimide suppresses MYC transcription in cancer cell lines derived from distinct tissues. Using renal cancer cells, we confirmed that stauprimide inhibits NME2 nuclear localization. Gene expression analysis also confirmed the selective down-regulation of MYC target genes by stauprimide. Consistent with this activity, administration of stauprimide inhibited tumor growth in rodent xenograft models. Our study provides a unique strategy for selectively targeting MYC transcription by pharmacological means as a potential treatment for MYCdependent tumors.MYC | stauprimide | NME2 | nuclear localization | cancer T he transcription factor MYC participates in diverse cellular processes by regulating the transcription of a large number of genes involved in gene expression, cell division, apoptosis, cell adhesion, stem cell self-renewal and differentiation, and metabolism (1-3). MYC is an oncogene whose expression is elevated in up to 75% of all cancers with various tissue origins (4); MYC expression levels also correlate with prognostic outcomes in patients of various types of malignancies (5, 6). In addition to its well-established roles in tumor initiation and cancer cell survival and proliferation, MYC has been shown to be involved in tumor microenvironment remodeling, drug resistance, and cancer stem cell maintenance (7-9). Recent studies have also revealed a role for MYC in regulating the transcription of immune checkpoint genes, including CD47 and PD-L1 in cancer cells, suggesting that MYC is involved in cancer escape from immune surveillance (10).Overexpression of MYC is able to induce malignant transformation in skin (11), lung (12), liver (13), breast (14, 15), and hematopoietic cells (16) in transgenic mouse models, and termination of MYC overexpression results in halted cancer cell proliferation, increased apoptosis and terminal differentiation, and tumor regression. Furthermore, inhibition of endogenous MYC by the inducible expression of a dominant-negative variant of MYC, Omomyc, is able to induce tumor regression in transgenic mouse models of lung cancer (17). More intriguingly, transient deactivation of MYC overexpression (18) and episodic expression of Omomyc (19) have been shown to induce irreversible tumor regression in osteosarcoma and lung cancer transgenic mouse models, suggesting the potential of MYCtargeted anticancer therapies.Drug discovery efforts have attempted to directly and indirectly modulate MYC-dependent transcription. For example, compounds have been identified that disrupt the interaction between MYC and its transcriptional partner MAX to suppress downstream gene transcription (20)(21)(22)(23)(2...

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“…These compounds Mycmycin-1 and Mycmycin-2 did not inhibit Jun dimerization and were a proof of concept to develop other molecules that specifically inhibit MYCinduced oncogenic transformation. 119 A new series of compounds, 10058-F4 and 10074-G5, were discovered using a two-hybrid system. 120 These compounds …”

Section: Blood and Lymphaticmentioning

confidence: 99%

MYC as therapeutic target in leukemia and lymphoma

Cortiguera¹,

Batlle-López²,

Albajar³

et al. 2015

BLCTT

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MYC is a transcription factor that is involved in the expression of many genes. Deregulated MYC is found in about half of human tumors, being more prevalent in hematological neoplasms. Deregulation mechanisms include chromosomal translocation (particularly in lymphoma), amplification, and hyperactivation of MYC transcription. Here we review MYC involvement in the major types of leukemia and lymphoma. MYC rearrangements appear in all Burkitt lymphomas and are common in other lymphoma types, whereas in acute lymphoblastic leukemia, acute myeloid leukemia, lymphoproliferative, and myeloproferative diseases, they are less frequent. However, MYC overexpression is present in all types of hematological malignancies and often correlates with a worse prognosis. Data in leukemia-derived cells and in animal models of lymphomagenesis and leukemogenesis suggest that MYC would be a good therapeutic target. Several MYC-directed therapies have been assayed in preclinical settings and even in clinical trials. First, peptides and small molecules that interrupt the MYC-MAX interaction impair MYCmediated tumorogenesis in several mouse models of solid tumors, although not yet in lymphoma and leukemia models. Second, there are a number of small molecules inhibiting the interaction of MYC-MAX heterodimers with DNA, still in the preclinical research phase. Third, inhibitors of MYC expression via the inhibition of BRD4 (a reader of acetylated histones) have been shown to control the growth of MYC-transformed leukemia and lymphoma cells and are being used in clinic trials. Finally, we review a number of promising MYC-mediated synthetic lethal approaches that are under study and have been tested in hematopoietic neoplasms.

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Small molecule inhibitors of Myc/Max dimerization and Myc-induced cell transformation

Abstract: The preparation and evaluation of a series of inhibitors of Myc—Max dimerization and Myc-induced cell transformation are described providing mycmycin-1 (3) and mycmycin-2 (4).

Cited by 49 publications

References 49 publications

In Vitro Cytotoxicity and In Vivo Efficacy, Pharmacokinetics, and Metabolism of 10074-G5, a Novel Small-Molecule Inhibitor of c-Myc/Max Dimerization

In Vitro Cytotoxicity and In Vivo Efficacy, Pharmacokinetics, and Metabolism of 10074-G5, a Novel Small-Molecule Inhibitor of c-Myc/Max Dimerization

Small molecule selectively suppresses MYC transcription in cancer cells

MYC as therapeutic target in leukemia and lymphoma

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