4cfk › Citations

The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains.

Dittmann A, Werner T, Chung CW, Savitski MM, Fälth Savitski M, Grandi P, Hopf C, Lindon M, Neubauer G, Prinjha RK, Bantscheff M, Drewes G
ACS Chem Biol 9 495-502 (2014)
Cited: 53 times
EuropePMC logo PMID: 24533473

Abstract

A commonly used small-molecule probe in cell-signaling research is the phosphoinositide 3-kinase inhibitor LY294002. Quantitative chemoproteomic profiling shows that LY294002 and LY303511, a close analogue devoid of PI3K activity, inhibit the BET bromodomain proteins BRD2, BRD3, and BRD4 that comprise a family of targets structurally unrelated to PI3K. Both compounds competitively inhibit acetyl-lysine binding of the first but not the second bromodomain of BET proteins in cell extracts. X-ray crystallography shows that the chromen-4-one scaffold represents a new bromodomain pharmacophore and establishes LY294002 as a dual kinase and BET-bromodomain inhibitor, whereas LY303511 exhibits anti-inflammatory and antiproliferative effects similar to the recently discovered BET inhibitors.

Reviews citing this publication (21)

  1. Targeting bromodomains: epigenetic readers of lysine acetylation. Filippakopoulos P, Knapp S. Nat Rev Drug Discov 13 337-356 (2014)
  2. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Fujisawa T, Filippakopoulos P. Nat Rev Mol Cell Biol 18 246-262 (2017)
  3. Drug Discovery Targeting Bromodomain-Containing Protein 4. Liu Z, Wang P, Chen H, Wold EA, Tian B, Brasier AR, Zhou J. J Med Chem 60 4533-4558 (2017)
  4. Targeting Cancer Cells with BET Bromodomain Inhibitors. Xu Y, Vakoc CR. Cold Spring Harb Perspect Med 7 a026674 (2017)
  5. Targeting BET bromodomains for cancer treatment. Jung M, Gelato KA, Fernández-Montalván A, Siegel S, Haendler B. Epigenomics 7 487-501 (2015)
  6. Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology. Blagg J, Workman P. Cancer Cell 32 9-25 (2017)
  7. Epigenetic drug discovery: breaking through the immune barrier. Tough DF, Tak PP, Tarakhovsky A, Prinjha RK. Nat Rev Drug Discov 15 835-853 (2016)
  8. Non-kinase targets of protein kinase inhibitors. Munoz L. Nat Rev Drug Discov 16 424-440 (2017)
  9. The emerging role of mass spectrometry-based proteomics in drug discovery. Meissner F, Geddes-McAlister J, Mann M, Bantscheff M. Nat Rev Drug Discov 21 637-654 (2022)
  10. Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology. Galdeano C, Ciulli A. Future Med Chem 8 1655-1680 (2016)
  11. Targeting bromodomain and extraterminal proteins in breast cancer. Sahni JM, Keri RA. Pharmacol Res 129 156-176 (2018)
  12. Molecular Pathways: Targeting the PI3K Pathway in Cancer-BET Inhibitors to the Rescue. Stratikopoulos EE, Parsons RE. Clin Cancer Res 22 2605-2610 (2016)
  13. Is There a Role for Dual PI3K/mTOR Inhibitors for Patients Affected with Lymphoma? Tarantelli C, Lupia A, Stathis A, Bertoni F. Int J Mol Sci 21 E1060 (2020)
  14. Dual-target inhibitors of bromodomain and extra-terminal proteins in cancer: A review from medicinal chemistry perspectives. Feng L, Wang G, Chen Y, Chen Y, He G, Liu B, Liu J, Chiang CM, Ouyang L. Med Res Rev 42 710-743 (2022)
  15. BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer. Nicholas DA, Andrieu G, Strissel KJ, Nikolajczyk BS, Denis GV. Cell Mol Life Sci 74 231-243 (2017)
  16. Epigenetic Mechanisms Regulating Adaptive Responses to Targeted Kinase Inhibitors in Cancer. Angus SP, Zawistowski JS, Johnson GL. Annu Rev Pharmacol Toxicol 58 209-229 (2018)
  17. Cutting Edge Therapeutic Insights Derived from Molecular Biology of Pediatric High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (DIPG). Bailey CP, Figueroa M, Mohiuddin S, Zaky W, Chandra J. Bioengineering (Basel) 5 E88 (2018)
  18. Studying epigenetic complexes and their inhibitors with the proteomics toolbox. Weigt D, Hopf C, Médard G. Clin Epigenetics 8 76 (2016)
  19. Review: Enhancers in Autoimmune Arthritis: Implications and Therapeutic Potential. Peeters JGC, Vastert SJ, van Wijk F, van Loosdregt J. Arthritis Rheumatol 69 1925-1936 (2017)
  20. Targeting bromodomain-containing proteins: research advances of drug discovery. Pan Z, Zhao Y, Wang X, Xie X, Liu M, Zhang K, Wang L, Bai D, Foster LJ, Shu R, He G. Mol Biomed 4 13 (2023)
  21. The magic of small-molecule drugs during ex vivo expansion in adoptive cell therapy. Zhang H, Passang T, Ravindranathan S, Bommireddy R, Jajja MR, Yang L, Selvaraj P, Paulos CM, Waller EK. Front Immunol 14 1154566 (2023)

Articles citing this publication (32)

  1. Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. Ciceri P, Müller S, O'Mahony A, Fedorov O, Filippakopoulos P, Hunt JP, Lasater EA, Pallares G, Picaud S, Wells C, Martin S, Wodicka LM, Shah NP, Treiber DK, Knapp S. Nat Chem Biol 10 305-312 (2014)
  2. Acetyl-lysine binding site of bromodomain-containing protein 4 (BRD4) interacts with diverse kinase inhibitors. Ember SW, Zhu JY, Olesen SH, Martin MP, Becker A, Berndt N, Georg GI, Schönbrunn E. ACS Chem Biol 9 1160-1171 (2014)
  3. The Bromodomain: A New Target in Emerging Epigenetic Medicine. Smith SG, Zhou MM. ACS Chem Biol 11 598-608 (2016)
  4. Click chemistry enables preclinical evaluation of targeted epigenetic therapies. Tyler DS, Vappiani J, Cañeque T, Lam EYN, Ward A, Gilan O, Chan YC, Hienzsch A, Rutkowska A, Werner T, Wagner AJ, Lugo D, Gregory R, Ramirez Molina C, Garton N, Wellaway CR, Jackson S, MacPherson L, Figueiredo M, Stolzenburg S, Bell CC, House C, Dawson SJ, Hawkins ED, Drewes G, Prinjha RK, Rodriguez R, Grandi P, Dawson MA. Science 356 1397-1401 (2017)
  5. Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis. Andrews FH, Singh AR, Joshi S, Smith CA, Morales GA, Garlich JR, Durden DL, Kutateladze TG. Proc Natl Acad Sci U S A 114 E1072-E1080 (2017)
  6. A chemical toolbox for the study of bromodomains and epigenetic signaling. Wu Q, Heidenreich D, Zhou S, Ackloo S, Krämer A, Nakka K, Lima-Fernandes E, Deblois G, Duan S, Vellanki RN, Li F, Vedadi M, Dilworth J, Lupien M, Brennan PE, Arrowsmith CH, Müller S, Fedorov O, Filippakopoulos P, Knapp S. Nat Commun 10 1915 (2019)
  7. Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B. Chen P, Chaikuad A, Bamborough P, Bantscheff M, Bountra C, Chung CW, Fedorov O, Grandi P, Jung D, Lesniak R, Lindon M, Müller S, Philpott M, Prinjha R, Rogers C, Selenski C, Tallant C, Werner T, Willson TM, Knapp S, Drewry DH. J Med Chem 59 1410-1424 (2016)
  8. Chemoproteomics Reveals Novel Protein and Lipid Kinase Targets of Clinical CDK4/6 Inhibitors in Lung Cancer. Sumi NJ, Kuenzi BM, Knezevic CE, Remsing Rix LL, Rix U. ACS Chem Biol 10 2680-2686 (2015)
  9. Single Agent and Synergistic Activity of the "First-in-Class" Dual PI3K/BRD4 Inhibitor SF1126 with Sorafenib in Hepatocellular Carcinoma. Singh AR, Joshi S, Burgoyne AM, Sicklick JK, Ikeda S, Kono Y, Garlich JR, Morales GA, Durden DL. Mol Cancer Ther 15 2553-2562 (2016)
  10. GSK2801, a BAZ2/BRD9 Bromodomain Inhibitor, Synergizes with BET Inhibitors to Induce Apoptosis in Triple-Negative Breast Cancer. Bevill SM, Olivares-Quintero JF, Sciaky N, Golitz BT, Singh D, Beltran AS, Rashid NU, Stuhlmiller TJ, Hale A, Moorman NJ, Santos CM, Angus SP, Zawistowski JS, Johnson GL. Mol Cancer Res 17 1503-1518 (2019)
  11. Nonequivalent response to bromodomain-targeting BET inhibitors in oligodendrocyte cell fate decision. Chiang CM. Chem Biol 21 804-806 (2014)
  12. Transcriptional Elongation of HSV Immediate Early Genes by the Super Elongation Complex Drives Lytic Infection and Reactivation from Latency. Alfonso-Dunn R, Turner AW, Jean Beltran PM, Arbuckle JH, Budayeva HG, Cristea IM, Kristie TM. Cell Host Microbe 21 507-517.e5 (2017)
  13. Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling. Bossler F, Kuhn BJ, Günther T, Kraemer SJ, Khalkar P, Adrian S, Lohrey C, Holzer A, Shimobayashi M, Dürst M, Mayer A, Rösl F, Grundhoff A, Krijgsveld J, Hoppe-Seyler K, Hoppe-Seyler F. mBio 10 e02323-18 (2019)
  14. Association of high microvessel αvβ3 and low PTEN with poor outcome in stage 3 neuroblastoma: rationale for using first in class dual PI3K/BRD4 inhibitor, SF1126. Erdreich-Epstein A, Singh AR, Joshi S, Vega FM, Guo P, Xu J, Groshen S, Ye W, Millard M, Campan M, Morales G, Garlich JR, Laird PW, Seeger RC, Shimada H, Durden DL. Oncotarget 8 52193-52210 (2017)
  15. Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity. Watts E, Heidenreich D, Tucker E, Raab M, Strebhardt K, Chesler L, Knapp S, Bellenie B, Hoelder S. J Med Chem 62 2618-2637 (2019)
  16. Status of KRAS in iPSCs Impacts upon Self-Renewal and Differentiation Propensity. Kubara K, Yamazaki K, Ishihara Y, Naruto T, Lin HT, Nishimura K, Ohtaka M, Nakanishi M, Ito M, Tsukahara K, Morio T, Takagi M, Otsu M. Stem Cell Reports 11 380-394 (2018)
  17. Suppression of interferon β gene transcription by inhibitors of bromodomain and extra-terminal (BET) family members. Malik N, Vollmer S, Nanda SK, Lopez-Pelaez M, Prescott A, Gray N, Cohen P. Biochem J 468 363-372 (2015)
  18. Synergistic effects of BET and MEK inhibitors promote regression of anaplastic thyroid tumors. Zhu X, Holmsen E, Park S, Willingham MC, Qi J, Cheng SY. Oncotarget 9 35408-35421 (2018)
  19. Image-based drug screen identifies HDAC inhibitors as novel Golgi disruptors synergizing with JQ1. Gendarme M, Baumann J, Ignashkova TI, Lindemann RK, Reiling JH. Mol Biol Cell 28 3756-3772 (2017)
  20. Membrane-bound SCF and VCAM-1 synergistically regulate the morphology of hematopoietic stem cells. Hao J, Zhou H, Nemes K, Yen D, Zhao W, Bramlett C, Wang B, Lu R, Shen K. J Cell Biol 220 e202010118 (2021)
  21. Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination. Rivera AD, Pieropan F, Williams G, Calzolari F, Butt AM, Azim K. Biomed Pharmacother 145 112436 (2022)
  22. Risk stratification for lung adenocarcinoma on EGFR and TP53 mutation status, chemotherapy, and PD-L1 immunotherapy. Wu CH, Hwang MJ. Cancer Med 8 5850-5861 (2019)
  23. A screening assay for the identification of host cell requirements and antiviral targets for hepatitis D virus infection. Buchmann B, Döhner K, Schirdewahn T, Sodeik B, Manns MP, Wedemeyer H, Ciesek S, von Hahn T. Antiviral Res 141 116-123 (2017)
  24. Chemosensitization of HT29 and HT29-5FU Cell Lines by a Combination of a Multi-Tyrosine Kinase Inhibitor and 5FU Downregulates ABCC1 and Inhibits PIK3CA in Light of Their Importance in Saudi Colorectal Cancer. Abdalla AN, Malki WH, Qattan A, Shahid I, Hossain MA, Ahmed M. Molecules 26 E334 (2021)
  25. Co-inhibition of BET proteins and PI3Kα triggers mitochondrial apoptosis in rhabdomyosarcoma cells. Boedicker C, Hussong M, Grimm C, Dolgikh N, Meister MT, Enßle JC, Wanior M, Knapp S, Schweiger MR, Fulda S. Oncogene 39 3837-3852 (2020)
  26. Design, synthesis and biological evaluation of novel pyrazolochalcones as potential modulators of PI3K/Akt/mTOR pathway and inducers of apoptosis in breast cancer cells. Shaik AB, Rao GK, Kumar GB, Patel N, Reddy VS, Khan I, Routhu SR, Kumar CG, Veena I, Chandra Shekar K, Barkume M, Jadhav S, Juvekar A, Kode J, Pal-Bhadra M, Kamal A. Eur J Med Chem 139 305-324 (2017)
  27. Inhibition of the acetyl lysine-binding pocket of bromodomain and extraterminal domain proteins interferes with adipogenesis. Goupille O, Penglong T, Kadri Z, Granger-Locatelli M, Fucharoen S, Maouche-Chrétien L, Prost S, Leboulch P, Chrétien S. Biochem Biophys Res Commun 472 624-630 (2016)
  28. Overexpression of microRNA-100-5p attenuates the endothelial cell dysfunction by targeting HIPK2 under hypoxia and reoxygenation treatment. Zheng H, Sun Y, Shu X, Gao Q, Chen X. J Mol Histol 52 1115-1125 (2021)
  29. Letter Epigenetic drug therapy based on bromodomain inhibition. Bayarsaihan D, Shin DG. Epigenomics 6 473-476 (2014)
  30. Congress 2016 EMBO Chemical Biology Conference. Virdee S. Chembiochem 18 66-71 (2017)
  31. Association of high microvessel αvβ3 and low PTEN with poor outcome in stage 3 neuroblastoma: rationale for using first in class dual PI3K/BRD4 inhibitor, SF1126. Erdreich-Epstein A, Singh AR, Joshi S, Vega FM, Guo P, Xu J, Groshen S, Ye W, Millard M, Campan M, Morales G, Garlich JR, Laird PW, Seeger RC, Shimada H, Durden DL. Oncotarget (2016)
  32. Rationally designed chimeric PI3K-BET bromodomain inhibitors elicit curative responses in MYC-driven lymphoma. Oh DH, Ma X, Hogg SJ, He J, Kearney C, Brasacchio D, Susanto O, Maher B, Jennings IG, Newbold A, Fraser P, Gruber E, Kats LM, Gregory GP, Johnstone RW, Thompson PE, Shortt J. Proc Natl Acad Sci U S A 120 e2306414120 (2023)


Quick links