Advertisement

Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer

  • Jiahui Xu
  • Qianqian Wang
  • Elaine Lai Han Leung
  • Ying Li
  • Xingxing Fan
  • Qibiao WuEmail author
  • Xiaojun YaoEmail author
  • Liang LiuEmail author
Research Article

Abstract

Bromodomain PHD-finger transcription factor (BPTF) is the largest subunit of the nucleosome remodeling factor and plays an important role in chromatin remodeling for gene activation through its association with histone acetylation or methylation. BPTF is also involved in oncogene transcription in diverse progressions of cancers. Despite clinical trials for inhibitors of bromodomain and extra-terminal family proteins in human cancers, no potent and selective inhibitor targeting the BPTF bromodomain has been discovered. In this study, we identified a potential inhibitor, namely, C620-0696, by computational docking modeling to target bromodomain. Results of biolayer interferometry revealed that compound C620-0696 exhibited high binding affinity to the BPTF bromodomain. Moreover, C620-0696 was cytotoxic in BPTF with a high expression of non-small-cell lung cancer (NSCLC) cells. It suppressed the expression of the BPTF target gene c-MYC, which is known as an oncogenic transcriptional regulator in various cancers. C620-0696 also partially inhibited the migration and colony formation of NSCLC cells owing to apoptosis induction and cell cycle blockage. Thus, our study presents an effective strategy to target a bromodomain factor-mediated tumorigenesis in cancers with small molecules, supporting further exploration of the use of these inhibitors in oncology.

Keywords

small molecule epigenetics non-small-cell lung cancer 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgements

This work was supported by Macao Science and Technology Development Fund (Nos. 102/2016/A3, 130/2017/A3, 0003/2018/A1, and 046/2016/A2).

Supplementary material

11684_2019_694_MOESM1_ESM.pdf (468 kb)
Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer

References

  1. 1.
    Spira A, Halmos B, Powell CA. Update in lung cancer 2015. Am J Respir Crit Care Med 2016; 194(6): 661–671Google Scholar
  2. 2.
    Alamgeer M, Ganju V, Watkins DN. Novel therapeutic targets in non-small cell lung cancer. Curr Opin Pharmacol 2013; 13(3): 394–401Google Scholar
  3. 3.
    Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer 2004; 4(2): 143–153Google Scholar
  4. 4.
    Chen QW, Zhu XY, Li YY, Meng ZQ. Epigenetic regulation and cancer (review). Oncol Rep 2014; 31(2): 523–532Google Scholar
  5. 5.
    You JS, Jones PA. Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell 2012; 22(1): 9–20Google Scholar
  6. 6.
    Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2010; 31(1): 27–36Google Scholar
  7. 7.
    Landry JW, Banerjee S, Taylor B, Aplan PD, Singer A, Wu C. Chromatin remodeling complex NURF regulates thymocyte maturation. Genes Dev 2011; 25(3): 275–286Google Scholar
  8. 8.
    Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004; 429(6990): 457–463Google Scholar
  9. 9.
    Cortez CC, Jones PA. Chromatin, cancer and drug therapies. Mutat Res 2008; 647(1–2): 44–51Google Scholar
  10. 10.
    Carew JS, Giles FJ, Nawrocki ST. Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett 2008; 269(1): 7–17Google Scholar
  11. 11.
    Datta J, Ghoshal K, Denny WA, Gamage SA, Brooke DG, Phiasivongsa P, Redkar S, Jacob ST. A new class of quinoline-based DNA hypomethylating agents reactivates tumor suppressor genes by blocking DNA methyltransferase 1 activity and inducing its degradation. Cancer Res 2009; 69(10): 4277–4285Google Scholar
  12. 12.
    Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M. Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov 2012; 11(5): 384–400Google Scholar
  13. 13.
    Gul S. Epigenetic assays for chemical biology and drug discovery. Clin Epigenetics 2017; 9(1): 41Google Scholar
  14. 14.
    Pérez-Salvia M, Esteller M. Bromodomain inhibitors and cancer therapy: from structures to applications. Epigenetics 2017; 12(5): 323–339Google Scholar
  15. 15.
    Filippakopoulos P, Knapp S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov 2014; 13(5): 337–356Google Scholar
  16. 16.
    Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Müller S, Pawson T, Gingras AC, Arrowsmith CH, Knapp S. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 2012; 149(1): 214–231Google Scholar
  17. 17.
    Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res 2011; 21(3): 381–395Google Scholar
  18. 18.
    Wadhwa E, Nicolaides T. Bromodomain inhibitor review: bromodomain and extra-terminal family protein inhibitors as a potential new therapy in central nervous system tumors. Cureus 2016; 8(5): e620Google Scholar
  19. 19.
    Ott CJ, Kopp N, Bird L, Paranal RM, Qi J, Bowman T, Rodig SJ, Kung AL, Bradner JE, Weinstock DM. BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood 2012; 120(14): 2843–2852Google Scholar
  20. 20.
    Lockwood WW, Zejnullahu K, Bradner JE, Varmus H. Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Proc Natl Acad Sci USA 2012; 109(47): 19408–19413Google Scholar
  21. 21.
    Sengupta S, Biarnes MC, Clarke R, Jordan VC. Inhibition of BET proteins impairs estrogen-mediated growth and transcription in breast cancers by pausing RNA polymerase advancement. Breast Cancer Res Treat 2015; 150(2): 265–278Google Scholar
  22. 22.
    Zhang L, Tong Y, Zhang X, Pan M, Chen S. Arsenic sulfide combined with JQ1, chemotherapy agents, or celecoxib inhibit gastric and colon cancer cell growth. Drug Des Devel Ther 2015; 9: 5851–5862Google Scholar
  23. 23.
    Mayes K, Qiu Z, Alhazmi A, Landry JW. ATP-dependentchromatin remodeling complexes as novel targets for cancer therapy. Adv Cancer Res 2014; 121: 183–233Google Scholar
  24. 24.
    Buganim Y, Goldstein I, Lipson D, Milyavsky M, Polak-Charcon S, Mardoukh C, Solomon H, Kalo E, Madar S, Brosh R, Perelman M, Navon R, Goldfinger N, Barshack I, Yakhini Z, Rotter V. A novel translocation breakpoint within the BPTF gene is associated with a pre-malignant phenotype. PLoS One 2010; 5(3): e9657Google Scholar
  25. 25.
    Jones MH, Hamana N, Shimane M. Identification and characterization of BPTF, a novel bromodomain transcription factor. Genomics 2000; 63(1): 35–39Google Scholar
  26. 26.
    Xiao S, Liu L, Lu X, Long J, Zhou X, Fang M. The prognostic significance of bromodomain PHD-finger transcription factor in colorectal carcinoma and association with vimentin and E-cadherin. J Cancer Res Clin Oncol 2015; 141(8): 1465–1474Google Scholar
  27. 27.
    Dar AA, Nosrati M, Bezrookove V, de Semir D, Majid S, Thummala S, Sun V, Tong S, Leong SP, Minor D, Billings PR, Soroceanu L, Debs R, Miller JR 3rd, Sagebiel RW, Kashani-Sabet M. The role of BPTF in melanoma progression and in response to BRAF-targeted therapy. J Natl Cancer Inst 2015; 107(5): djv034Google Scholar
  28. 28.
    Dar AA, Majid S, Bezrookove V, Phan B, Ursu S, Nosrati M, De Semir D, Sagebiel RW, Miller JR 3rd, Debs R, Cleaver JE, Kashani-Sabet M. BPTF transduces MITF-driven prosurvival signals in melanoma cells. Proc Natl Acad Sci USA 2016; 113(22): 6254–6258Google Scholar
  29. 29.
    Mayes K, Alkhatib SG, Peterson K, Alhazmi A, Song C, Chan V, Blevins T, Roberts M, Dumur CI, Wang XY, Landry JW. BPTF depletion enhances T-cell-mediated antitumor immunity. Cancer Res 2016; 76(21): 6183–6192Google Scholar
  30. 30.
    Xu B, Cai L, Butler JM, Chen D, Lu X, Allison DF, Lu R, Rafii S, Parker JS, Zheng D, Wang GG. The chromatin remodeler BPTF activates a stemness gene-expression program essential for the maintenance of adult hematopoietic stem cells. Stem Cell Reports 2018; 10(3): 675–683Google Scholar
  31. 31.
    Dang CV, Le A, Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res 2009; 15(21): 6479–6483Google Scholar
  32. 32.
    Johnson BE, Ihde DC, Makuch RW, Gazdar AF, Carney DN, Oie H, Russell E, Nau MM, Minna JD. myc family oncogene amplification in tumor cell lines established from small cell lung cancer patients and its relationship to clinical status and course. J Clin Invest 1987; 79(6): 1629–1634Google Scholar
  33. 33.
    Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, Mitsiades CS. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011; 146(6): 904–917Google Scholar
  34. 34.
    Gallagher SJ, Tiffen JC, Hersey P. Histone modifications, modifiers and readers in melanoma resistance to targeted and immune therapy. Cancers (Basel) 2015; 7(4): 1959–1982Google Scholar
  35. 35.
    Kim K, Punj V, Choi J, Heo K, Kim JM, Laird PW, An W. Gene dysregulation by histone variant H2A.Z in bladder cancer. Epigenetics Chromatin 2013; 6(1): 34Google Scholar
  36. 36.
    Shi X, Mihaylova VT, Kuruvilla L, Chen F, Viviano S, Baldassarre M, Sperandio D, Martinez R, Yue P, Bates JG, Breckenridge DG, Schlessinger J, Turk BE, Calderwood DA. Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms. Proc Natl Acad Sci USA 2016; 113(31): E4558–E4566Google Scholar
  37. 37.
    Ruthenburg AJ, Li H, Milne TA, Dewell S, McGinty RK, Yuen M, Ueberheide B, Dou Y, Muir TW, Patel DJ, Allis CD. Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions. Cell 2011; 145(5): 692–706Google Scholar
  38. 38.
    Wysocka J, Swigut T, Xiao H, Milne TA, Kwon SY, Landry J, Kauer M, Tackett AJ, Chait BT, Badenhorst P, Wu C, Allis CD. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 2006; 442(7098): 86–90Google Scholar
  39. 39.
    Li H, Ilin S, Wang W, Duncan EM, Wysocka J, Allis CD, Patel DJ. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 2006; 442(7098): 91–95Google Scholar
  40. 40.
    Richart L, Carrillo-de Santa Pau E, Río-Machín A, de Andrés MP, Cigudosa JC, Lobo VJ, Real FX. BPTF is required for c-MYC transcriptional activity and in vivo tumorigenesis. Nat Commun 2016; 7(1): 10153Google Scholar
  41. 41.
    Kagoya Y, Nakatsugawa M, Yamashita Y, Ochi T, Guo T, Anczurowski M, Saso K, Butler MO, Arrowsmith CH, Hirano N. BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models. J Clin Invest 2016; 126(9): 3479–3494Google Scholar
  42. 42.
    Dai M, Lu JJ, Guo W, Yu W, Wang Q, Tang R, Tang Z, Xiao Y, Li Z, Sun W, Sun X, Qin Y, Huang W, Deng WG, Wu T. BPTF promotes tumor growth and predicts poor prognosis in lung adenocarcinomas. Oncotarget 2015; 6(32): 33878–33892Google Scholar
  43. 43.
    Wang Q, Xu J, Li Y, Huang J, Jiang Z, Wang Y, Liu L, Leung ELH, Yao X. Identification of a novel protein arginine methyltransferase 5 inhibitor in non-small cell lung cancer by structure-based virtual screening. Front Pharmacol 2018; 9: 173Google Scholar
  44. 44.
    Urick AK, Hawk LM, Cassel MK, Mishra NK, Liu S, Adhikari N, Zhang W, dos Santos CO, Hall JL, Pomerantz WC. Dual screening of BPTF and Brd4 using protein-observed fluorine NMR uncovers new bromodomain probe molecules. ACS Chem Biol 2015; 10(10): 2246–2256Google Scholar
  45. 45.
    Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M, Coleman B, Sebree R, Rodgers K, Hooker CM, Franco N, Lee B, Tsai S, Delgado IE, Rudek MA, Belinsky SA, Herman JG, Baylin SB, Brock MV, Rudin CM. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov 2011; 1(7): 598–607Google Scholar
  46. 46.
    Wang GG, Allis CD, Chi P. Chromatin remodeling and cancer, Part II: ATP-dependent chromatin remodeling. Trends Mol Med 2007; 13(9): 373–380Google Scholar
  47. 47.
    Shiraishi K, Kunitoh H, Daigo Y, Takahashi A, Goto K, Sakamoto H, Ohnami S, Shimada Y, Ashikawa K, Saito A, Watanabe S, Tsuta K, Kamatani N, Yoshida T, Nakamura Y, Yokota J, Kubo M, Kohno T. A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population. Nat Genet 2012; 44(8): 900–903Google Scholar
  48. 48.
    Gong YC, Liu DC, Li XP, Dai SP. BPTF biomarker correlates with poor survival in human NSCLC. Eur Rev Med Pharmacol Sci 2017; 21(1): 102–107Google Scholar
  49. 49.
    Hynes NE, Stoelzle T. Key signalling nodes in mammary gland development and cancer: Myc. Breast Cancer Res 2009; 11(5): 210Google Scholar

Copyright information

© Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and HealthMacau University of Science and TechnologyMacau (SAR)China
  2. 2.Respiratory Medicine Department, Taihe HospitalHubei University of MedicineShiyanChina
  3. 3.Department of Thoracic Surgery, Guangzhou Institute of Respiratory Health and State Key Laboratory of Respiratory DiseaseThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina

Personalised recommendations