2019
DOI: 10.1021/jacs.9b02679
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Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC

Abstract: MYC is one of the most important oncogenes and is overexpressed in the majority of cancers. Gquadruplexes are noncanonical four-stranded DNA secondary structures that have emerged as attractive cancer-specific molecular targets for drug development. The G-quadruplex formed in the proximal promoter region of the MYC oncogene (MycG4) has been shown to be a transcriptional silencer that is amenable to small molecule targeting for MYC suppression. Indenoisoquinolines

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Cited by 82 publications
(75 citation statements)
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References 85 publications
(178 reference statements)
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“…A similar 2 : 1 ligand : c-MYC Pu22 complex was earlier reported for quindoline and indenoisoquinolines compounds. 31,32 The association constant calculated for 4b-c-MYC Pu22 complex is among the highest values reported in literature so far. [21][22][23][24] Moreover, a limit of detection (LOD) of 49 nM was obtained which is 2-fold lower than that reported for N-methyl mesoporphyrin IX (NMM), a renowned selective parallel G4 binder, LOD = 104 nM (Fig.…”
Section: G4-interactive Binding Studiesmentioning
confidence: 93%
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“…A similar 2 : 1 ligand : c-MYC Pu22 complex was earlier reported for quindoline and indenoisoquinolines compounds. 31,32 The association constant calculated for 4b-c-MYC Pu22 complex is among the highest values reported in literature so far. [21][22][23][24] Moreover, a limit of detection (LOD) of 49 nM was obtained which is 2-fold lower than that reported for N-methyl mesoporphyrin IX (NMM), a renowned selective parallel G4 binder, LOD = 104 nM (Fig.…”
Section: G4-interactive Binding Studiesmentioning
confidence: 93%
“…[27][28][29][30] The truncated c-MYC Pu22 sequence (c-MYC Pu22, 5′-TGAG 3 TG 3 TAG 3 TG 3 TTA-3′) form the major G4 conformation representing the wild-type G4 found in the NHEIII1 region of the c-MYC gene and provides a great molecular system for G4interactive binding studies. 31 To investigate if the emission enhancement of 4b in the presence of c-MYC Pu22 was specific to only this ligand, we examined the G4 light-up binding response of all the synthesized compounds (3a-4d) in the presence of c-MYC Pu22. As depicted in Fig.…”
Section: G4-interactive Binding Studiesmentioning
confidence: 99%
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“…Furthermore, JQ1, a BET (bromodomain and extra-terminal domain) inhibitor, can also inhibit MYC transcription, as well as other pathways [62] . We and others have focused on interfering with MYC gene transcription by an alternative inhibitory mechanism involving small molecules that stabilize complex DNA structures (G-quadruplexes) which form transiently in the MYC promoter [26,27,63,64] .…”
Section: Resultsmentioning
confidence: 99%
“…It has been found that the Gquadruplex forming guanine-rich sequences widely exist in many regions of chromosomes [12], such as telomeres [13], promoters of oncogenes [14], immunoglobulin switches [15] and the insulin regulatory regions [16]. Particularly, the promoter of oncogene c-myc, which is overexpressed in up to 80% of solid tumors, but has low expression in normal cells, can also form a Gquadruplex conformation via Hoogesten hydrogen bonds, and is closely related to the proliferation, apoptosis, cell-cycle arrest, invasion and metastasis of tumor cells [17][18][19].…”
Section: Introductionmentioning
confidence: 99%