靶向肿瘤因子c-MYC基因启动区G4-DNA的小分子药物设计及核磁共振研究进展
收稿日期: 2021-06-29
网络出版日期: 2021-11-01
基金资助
国家重点研发计划资助项目(2017YFE0108200);国家自然科学基金资助项目(21977110);国家自然科学基金资助项目(21778065);国家自然科学基金资助项目(21807105);中国科学院先导项目(XDB20000000);中国科学院分子合成卓越中心资助项目(FZHCZY020600)
Research Advance and NMR Studies of Anti-Cancer Small Molecules Targeting c-MYC G4-DNA
Received date: 2021-06-29
Online published: 2021-11-01
肿瘤基因MYC在人类70%癌细胞中高表达，抑制其转录是治疗肿瘤的有效手段.c-MYC启动子区P1近端的核酸酶超敏元件Ⅲ1(NHE Ⅲ1)控制MYC基因近90%的转录激活.NHE Ⅲ1区域富含碱基G序列并且形成G-四链体(G4)，调控c-MYC基因转录，是抗肿瘤药物靶标.但G4-DNA和G4-RNA的三维结构高度相似，小分子与其他G4(如端粒G4、mRNA G4、c-Kit G4等)的非特异性作用会产生小分子药物“脱靶”效应，同时小分子药物会诱导其他G4形成从而干扰正常细胞的功能，造成靶向c-MYC G4抗癌药物设计困难.本文综述了近些年靶向肿瘤因子c-MYC G4-DNA的小分子药物研究进展，及核磁共振(NMR)技术在G4-DNA和G4-RNA结构确定中的作用，为靶向c-MYC G4-DNA的小分子药物设计等相关研究工作提供参考.
胡晓东 , 蓝文贤 , 王春喜 , 曹春阳 . 靶向肿瘤因子c-MYC基因启动区G4-DNA的小分子药物设计及核磁共振研究进展[J]. 波谱学杂志, 2021 , 38(4) : 503 -513 . DOI: 10.11938/cjmr20212928
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.
| 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. |
| 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. |
| 3 | ADRIAN M , HEDDI B , PHAN A T . NMR spectroscopy of G-quadruplexes[J]. Methods, 2012, 57 (1): 11- 24. |
| 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. |
| 6 | LIPPS H J , RHODES D . G-quadruplex structures: in vivo evidence and function[J]. Trends Cell Biol, 2009, 19 (8): 414- 422. |
| 7 | TORNALETTI S . Transcriptional processing of G4 DNA[J]. Mol Carcinog, 2009, 48 (4): 326- 335. |
| 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. |
| 9 | TOMONAGA T , LEVENS D . Activating transcription from single stranded DNA[J]. Proc Natl Acad Sci U S A, 1996, 93, 5830- 5835. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 21 | PETR M , HELMA R , POLá?KOVá A , et al. Wild-type p53 binds to MYC promoter G-quadruplex[J]. Biosci Rep, 2016, 36 (5): e00397. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 53 | ALZEER J , LUEDTKE N W . pH-mediated fluorescence and G-quadruplex binding of amido phthalocyanines[J]. Biochemistry, 2010, 49 (20): 4339- 4348. |
| 54 | VORLICKOVA M , KEJNOVSKá I , SAGI J , et al. Circular dichroism and guanine quadruplexes[J]. Methods, 2012, 57 (1): 64- 75. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
/
| 〈 |
|
〉 |