Research Advance and NMR Studies of Anti-Cancer Small Molecules Targeting c-MYC G4-DNA

doi:10.11938/cjmr20212928

Abstract

Abstract:

MYC is a highly expressed oncogene in about 70% of human cancer cells and inhibition of its transcription serves as an effective tumor treatment. The P1 proximal nuclease hypersensitive element (NHE) Ⅲ₁ of c-MYC promoter region controls nearly 90% transcriptional activation of MYC gene. This region enriched with base G forms G-quadruplex (G4) structure, which regulates c-MYC gene transcription and is a target of anti-tumor drugs. However, the three-dimensional structures of G4-DNA and G4-RNA are highly similar. Non-specific interactions between small molecules and other G4s, such as telomere G4, mRNA G4, c-Kit G4, etc., yield "off-target" effects. Meanwhile, small molecules can induce the formation of other G4s, thus interfering with the function of normal cells. All of these hinder the design of anti-cancer drugs targeting c-MYC G4. In this paper, we summarize the recent research progress of small molecules targeting tumor factor c-MYC G4-DNA, and the role of nuclear magnetic resonance (NMR) in determining G4-DNA and G4-RNA structure. This review provides a reference for designing drugs targeting c-MYC G4-DNA and other related research works.

Key words: tumor gene, c-MYC, G-quadruplex (G4), small molecular drug, nuclear magnetic resonance (NMR)

CLC Number:

O482.53

Xiao-dong HU,Wen-xian LAN,Chun-xi WANG,Chun-yang CAO. Research Advance and NMR Studies of Anti-Cancer Small Molecules Targeting c-MYC G4-DNA[J]. Chinese Journal of Magnetic Resonance, 2021, 38(4): 503-513.

Figures/Tables 11

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References 62

1	WELLS R D , DERE R , HEBERT M L , et al. Advances in mechanisms of genetic instability related to hereditary neurological diseases[J]. Nucleic Acids Res, 2005, 33 (12): 3785- 3798. doi: 10.1093/nar/gki697
2	GELLERT M , LIPSETT M N , DAVIES D R . Helix formation by guanylic acid[J]. Proc Natl Acad Sci U S A, 1962, 48 (12): 2013- 2018. doi: 10.1073/pnas.48.12.2013
3	ADRIAN M , HEDDI B , PHAN A T . NMR spectroscopy of G-quadruplexes[J]. Methods, 2012, 57 (1): 11- 24. doi: 10.1016/j.ymeth.2012.05.003
4	HUPPERT J L . Four-stranded nucleic acids: structure, function and targeting of G-quadruplexes[J]. Chem Soc Rev, 2008, 39 (40): 1375- 1384.
5	BALASUBRAMANIAN S , HURLEY L H , NEIDLE S . Targeting G-quadruplexes in gene promoters: a novel anticancer strategy?[J]. Nat Rev Drug Discov, 2011, 10, 261- 275. doi: 10.1038/nrd3428
6	LIPPS H J , RHODES D . G-quadruplex structures: in vivo evidence and function[J]. Trends Cell Biol, 2009, 19 (8): 414- 422. doi: 10.1016/j.tcb.2009.05.002
7	TORNALETTI S . Transcriptional processing of G4 DNA[J]. Mol Carcinog, 2009, 48 (4): 326- 335. doi: 10.1002/mc.20513
8	COONEY M , CZERNUSZEWICZ G , POSTEL E H , et al. Site-specific oligonucleotide binding represses transcription of the human c-myc gene in vitro[J]. Science, 1988, 241 (4864): 456- 459. doi: 10.1126/science.3293213
9	TOMONAGA T , LEVENS D . Activating transcription from single stranded DNA[J]. Proc Natl Acad Sci U S A, 1996, 93, 5830- 5835. doi: 10.1073/pnas.93.12.5830
10	SEENISAMY J , BASHYAM S , GOKHALE V , et al. Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure[J]. J Am Chem Soc, 2005, 127 (9): 2944- 2959. doi: 10.1021/ja0444482
11	SIDDIQUI-JAIN A , GRAND C L , BEARSS D J , et al. Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription[J]. Proc Natl Acad Sci U S A, 2002, 99, 11593- 11598. doi: 10.1073/pnas.182256799
12	SUN Z Y , WANG X N , CHENG S Q , et al. Developing novel G-quadruplex ligands: from interaction with nucleic acids to interfering with nucleic acid(-)protein interaction[J]. Molecules, 2019, 24 (3): 396. doi: 10.3390/molecules24030396
13	BRAZDA V , HARONIKOVA L , LIAO J C , et al. DNA and RNA quadruplex-binding proteins[J]. Int J Mol Sci, 2014, 15, 17493- 17517. doi: 10.3390/ijms151017493
14	VARSHNEY D , SPIEGEL J , ZYNER K , et al. The regulation and functions of DNA and RNA G-quadruplexes[J]. Nat Rev Mol Cell Biol, 2020, 21, 459- 474. doi: 10.1038/s41580-020-0236-x
15	GONZALEZ V , GUO K X , HURLEY L , et al. Identification and characterization of nucleolin as a c-MYC G-quadruplex-binding protein[J]. J Biol Chem, 2009, 284 (35): 23622- 23635. doi: 10.1074/jbc.M109.018028
16	GONZALEZ V , HURLEY L H . The C-terminus of nucleolin promotes the formation of the c-MYC G-quadruplex and inhibits c-MYC promoter activity[J]. Biochemistry, 2010, 49 (45): 9706- 9714. doi: 10.1021/bi100509s
17	FEDERICI L , ARCOVITO A , SCAGLIONE G L , et al. Nucleophosmin C-terminal leukemia-associated domain interacts with G-rich quadruplex forming DNA[J]. J Biol Chem, 2010, 285 (48): 37138- 37149. doi: 10.1074/jbc.M110.166736
18	Scognamiglio P L , Di Natale C , Leone M , et al. G-quadruplex DNA recognition by nucleophosmin: new insights from protein dissection[J]. Biochim Biophys Acta, 2014, 1840 (6): 2050- 2059. doi: 10.1016/j.bbagen.2014.02.017
19	GALLO A , STERZO CL , MORI M , et al. Structure of nucleophosmin DNA-binding domain and analysis of its complex with a G-quadruplex sequence from the c-MYC promoter[J]. J Biol Chem, 2012, 287 (32): 26539- 26548. doi: 10.1074/jbc.M112.371013
20	KANG H J , LE TVT , KIM K , et al. Novel interaction of the Z-DNA binding domain of human ADAR1 with the oncogenic c-MYC promoter G-quadruplex[J]. J Mol Biol, 2014, 426 (14): 2594- 2604. doi: 10.1016/j.jmb.2014.05.001
21	PETR M , HELMA R , POLÁŠKOVÁ A , et al. Wild-type p53 binds to MYC promoter G-quadruplex[J]. Biosci Rep, 2016, 36 (5): e00397. doi: 10.1042/BSR20160232
22	SANDERS C M . Human Pif1 helicase is a G-quadruplex DNA-binding protein with G-quadruplex DNA-unwinding activity[J]. Biochem J, 2010, 430, 119- 128. doi: 10.1042/BJ20100612
23	BYRD A K , RANEY K D . A parallel quadruplex DNA is bound tightly but unfolded slowly by pif1 helicase[J]. J Biol Chem, 2015, 290 (10): 6482- 6494. doi: 10.1074/jbc.M114.630749
24	BYRD A K , BELL M R , RANEY K D . Pif1 helicase unfolding of G-quadruplex DNA is highly dependent on sequence and reaction conditions[J]. J Biol Chem, 2018, 293 (46): 17792- 17802. doi: 10.1074/jbc.RA118.004499
25	LEE S , LEE A R , RYU K S , et al. NMR investigation of the interaction between the RecQ C-terminal domain of human bloom syndrome protein and G-quadruplex DNA from the human c-MYC promoter[J]. J Mol Biol, 2019, 431 (4): 794- 806. doi: 10.1016/j.jmb.2019.01.010
26	BUDHATHOKI J B , RAY S , URBAN V , et al. RecQ-core of BLM unfolds telomeric G-quadruplex in the absence of ATP[J]. Nucleic Acids Res, 2014, 42 (18): 11528- 11545. doi: 10.1093/nar/gku856
27	CHATTERJEE S , ZAGELBAUM J , SAVITSKY P , et al. Mechanistic insight into the interaction of BLM helicase with intra-strand G-quadruplex structures[J]. Nat Commun, 2014, 5, 5556. doi: 10.1038/ncomms6556
28	KAROW J K , WU L , HICKSON I D . RecQ family helicases: roles in cancer and aging[J]. Curr Opin Genet Dev, 2000, 10 (1): 32- 38. doi: 10.1016/S0959-437X(99)00039-8
29	SUN H , KAROW J K. , HICKSON I D , et al. The Bloom's syndrome helicase unwinds G4 DNA[J]. J Biol Chem, 1998, 273 (42): 27587- 27592. doi: 10.1074/jbc.273.42.27587
30	WU G H , XING Z , TRAN E J , et al. DDX5 helicase resolves G-quadruplex and is involved in MYC gene transcriptional activation[J]. Proc Natl Acad Sci U S A, 2019, 116 (41): 20453- 20461. doi: 10.1073/pnas.1909047116
31	POSTEL E H , BERBERICH S J , FLINT S J , et al. Human c-MYC transcription factor PuF identified as nm23-H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis[J]. Science, 1993, 261 (5120): 478- 480. doi: 10.1126/science.8392752
32	JI L , ARCINAS M , BOXER L M . The transcription factor, Nm23H2, binds to and activates the translocated c-MYC allele in Burkitt's lymphoma[J]. J Biol Chem, 1995, 270 (22): 13392- 13398. doi: 10.1074/jbc.270.22.13392
33	FEKETE A , KENESI E , HUNYADI-GULYAS E , et al. The guanine-quadruplex structure in the human c-myc gene's promoter is converted into B-DNA form by the human poly(ADP-ribose)polymerase-1[J]. PLoS One, 2012, 7, e42690. doi: 10.1371/journal.pone.0042690
34	OU T M , LIN J , LU Y J , et al. Inhibition of cell proliferation by quindoline derivative (SYUIQ-05) through its preferential interaction with c-MYC promoter G-quadruplex[J]. J Med Chem, 2011, 54 (16): 5671- 5679. doi: 10.1021/jm200062u
35	DAI J X , CARVER M , HURLEY L H , et al. Solution structure of a 2:1 quindoline-c-MYC G-quadruplex: insights into G-quadruplex-interactive small molecule drug design[J]. J Am Chem Soc, 2011, 133 (44): 17673- 17680. doi: 10.1021/ja205646q
36	ZENG D Y , KUANG G T , WANG S K , et al. Discovery of Novel 11-triazole substituted benzofuro[3, 2-b]quinolone derivatives as c-MYC G-quadruplex specific stabilizers via click chemistry[J]. J Med Chem, 2017, 60, 5407- 5423. doi: 10.1021/acs.jmedchem.7b00016
37	LIU H Y , CHEN A C , YIN Q K , et al. New Disubstituted quindoline derivatives inhibiting Burkitt's lymphoma cell proliferation by impeding c-MYC transcription[J]. J Med Chem, 2017, 60 (13): 5438- 5454. doi: 10.1021/acs.jmedchem.7b00099
38	GABELICA V , BAKER E S , TEULADE-FICHOU M P , et al. Stabilization and structure of telomeric and c-MYC region intramolecular G-quadruplexes: the role of central cations and small planar ligands[J]. J Am Chem Soc, 2007, 129 (4): 895- 904. doi: 10.1021/ja065989p
39	GRAND C L , HAN H Y , MUNOZ R M , et al. The cationic porphyrin TMPyP4 down-regulates c-MYC and human telomerase reverse transcriptase expression and inhibits tumor growth in vivo[J]. Mol Cancer Ther, 2002, 1, 565- 573.
40	SEENISAMY J , REZLER E M , POWELL T J , et al. The dynamic character of the G-quadruplex element in the c-MYC promoter and modification by TMPyP4[J]. J Am Chem Soc, 2004, 126 (28): 8702- 8709. doi: 10.1021/ja040022b
41	PHAN A T , KURYAVYI V , GAW H Y , et al. Small-molecule interaction with a five-guanine-tract G-quadruplex structure from the human MYC promoter[J]. Nat Chem Biol, 2005, 1, 167- 173. doi: 10.1038/nchembio723
42	HU M H , WANG Y Q , YU Z Y , et al. Discovery of a new four-leaf clover-like ligand as a potent c-MYC transcription inhibitor specifically targeting the promoter G-quadruplex[J]. J Med Chem, 2018, 61 (6): 2447- 2459. doi: 10.1021/acs.jmedchem.7b01697
43	WU T Y , HUANG Q , HUANG Z S , et al. A drug-like imidazole-benzothiazole conjugate inhibits malignant melanoma by stabilizing the c-MYC G-quadruplex[J]. Bioorg Chem, 2020, 99, 103866. doi: 10.1016/j.bioorg.2020.103866
44	HU M H , WU T Y , HUANG Q , et al. New substituted quinoxalines inhibit triple-negative breast cancer by specifically downregulating the c-MYC transcription[J]. Nucleic Acids Res, 2019, 47 (20): 10529- 10542. doi: 10.1093/nar/gkz835
45	GLUSZYNSKA A , JUSKOWIAK B , KUTA-SIEJKOWSKA M , et al. Carbazole ligands as c-MYC G-quadruplex binders[J]. Int J Biol Macromol, 2018, 114, 479- 490. doi: 10.1016/j.ijbiomac.2018.03.135
46	DAS T , PANDA D , SAHA P , et al. Small molecule driven stabilization of promoter G-quadruplexes and transcriptional regulation of c-MYC[J]. Bioconjug Chem, 2018, 29 (8): 2636- 2645. doi: 10.1021/acs.bioconjchem.8b00338
47	SCHMIDT A W , REDDY K R , KNOLKER H J . Occurrence, biogenesis, and synthesis of biologically active carbazole alkaloids[J]. Chem Rev, 2012, 112 (6): 3193- 3328. doi: 10.1021/cr200447s
48	MA Y , OU T M , HOU J Q , et al. 9-N-substituted berberine derivatives: stabilization of G-quadruplex DNA and down-regulation of oncogene c-MYC[J]. Bioorg Med Chem, 2008, 16 (16): 7582- 7591. doi: 10.1016/j.bmc.2008.07.029
49	PENG D , TAN J H , CHEN S B , et al. Bisaryldiketene derivatives: A new class of selective ligands for c-myc G-quadruplex DNA[J]. Bioorg Med Chem, 2010, 18 (23): 8235- 8242. doi: 10.1016/j.bmc.2010.10.021
50	SHAN C , YAN J W , WANG Y Q , et al. Design, synthesis, and evaluation of isaindigotone derivatives to downregulate c-MYC transcription via disrupting the interaction of NM23-H2 with G-quadruplex[J]. J Med Chem, 2017, 60 (4): 1292- 1308. doi: 10.1021/acs.jmedchem.6b01218
51	Islam M M , Fujii S , Sato S , et al. A selective G-quadruplex DNA-stabilizing ligand based on a cyclic naphthalene diimide derivative[J]. Molecules, 2015, 20, 10963- 10979. doi: 10.3390/molecules200610963
52	CHAN D S H , YANG H , KWAN M H T , et al. Structure-based optimization of FDA-approved drug methylene blue as a c-MYC G-quadruplex DNA stabilizer[J]. Biochimie, 2011, 93 (6): 1055- 1064. doi: 10.1016/j.biochi.2011.02.013
53	ALZEER J , LUEDTKE N W . pH-mediated fluorescence and G-quadruplex binding of amido phthalocyanines[J]. Biochemistry, 2010, 49 (20): 4339- 4348. doi: 10.1021/bi9020583
54	VORLICKOVA M , KEJNOVSKÁ I , SAGI J , et al. Circular dichroism and guanine quadruplexes[J]. Methods, 2012, 57 (1): 64- 75. doi: 10.1016/j.ymeth.2012.03.011
55	SEN D , GILBERT W . Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis[J]. Nature, 1988, 334, 364- 366. doi: 10.1038/334364a0
56	MARCHAND A , FERREIRA R , TATEISHI-KARIMATA H , et al. Sequence and solvent effects on telomeric DNA bimolecular G-quadruplex folding kinetics[J]. J Phys Chem B, 2013, 117 (41): 12391- 12401. doi: 10.1021/jp406857s
57	TONG X T , LAN W X , ZHANG X , et al. Solution structure of all parallel G-quadruplex formed by the oncogene RET promoter sequence[J]. Nucleic Acids Res, 2011, 39 (15): 6753- 6763. doi: 10.1093/nar/gkr233
58	LI M M , WU S , LIU Z , et al. Arenobufagin, a bufadienolide compound from toad venom, inhibits VEGF-mediated angiogenesis through suppression of VEGFR-2 signaling pathway[J]. Biochem Pharmacol, 2012, 83 (9): 1251- 1260. doi: 10.1016/j.bcp.2012.01.023
59	LIU Y P , LAN W X , WANG C X , et al. A putative G-quadruplex structure in the proximal promoter of VEGFR-2 has implications for drug design to inhibit tumor angiogenesis[J]. J Biol Chem, 2018, 293 (23): 8947- 8955. doi: 10.1074/jbc.RA118.002666
60	CALABRESE D R , CHEN X , LEON E C , et al. Chemical and structural studies provide a mechanistic basis for recognition of the MYC G-quadruplex[J]. Nat Commun, 2018, 9, 4229. doi: 10.1038/s41467-018-06315-w
61	WANG F , WANG C X , LIU Y P , et al. Colchicine selective interaction with oncogene RET G-quadruplex revealed by NMR[J]. Chem Commun (Camb), 2020, 56 (14): 2099- 2102. doi: 10.1039/D0CC00221F
62	WANG F , WANG C X , LIU Y P , et al. NMR studies on the interaction between oncogene RET G-quadruplex and berberine[J]. Chinese J Chem, 2020, 38 (12): 1656- 1662. doi: 10.1002/cjoc.202000301

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