MZ1
BET proteins BRD4, BRD3, BRD2

MZ1

Protein Target(s) Name: BET proteins BRD4, BRD3, BRD2

Mechanism of Action: PROTAC degrader

Description: VH032 (VHL) based and (+)-JQ1 based PROTAC that degrades BET proteins in cells and in vivo. MZ1 exhibits preferential degradation of BRD4 at nM concentrations (1).

Chemical Name: (2S,4R)-1-((S)-2-(tert-butyl)-17-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-4,16-dioxo-6,9,12-trioxa-3,15-diazaheptadecanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

CAS Number: 1797406-69-9

In vitro pharmacology*: MZ1 reduces BET protein levels in human cells: Brd4 pDC50 | Dmax (%) in HeLa cells (24 h) = 8.6 | 100
MZ1 shows antiproliferative and Myc-suppression activity in AML MV4;11 and HL60 cells: pEC50 in MV4;11 | HL-60 cells (48 h) = 7.6 | 6.7
Data from ref. (3)

*DC50: concentration in molar causing 50% reduction of protein level relative to vehicle control treatment.
Dmax: maximum reduction of protein level relative to vehicle control treatment.
EC50: effective concentration in molar causing 50% reduction of cell viability relative to vehicle control treatment.

Biophysical binding data: ITC binary Kd (Brd4-BD2) = 15 nM; ITC binary Kd (VHL) = 66 nM; ITC ternary Kd (VHL, in the presence of Brd4-BD2) = 3.7 nM; cooperativity (alpha) = 18. Ternary complex stability DeltaG = -22.2 kcal/mol. Data from ref. (2)
Ternary complex VHL:MZ1:Brd4-BD2 t1/2 (SPR) = 130 s. FP ternary Kd (VHL, in the presence of Brd4-BD2) = 1.3 nM. Data from ref. (4)

In vivo PK data: MZ1 is suitable for a parenteral administration (i.v., i.p. or s.c.). The compound shows high clearance in rats and low clearance in mice. High AUC levels can be obtained, when the compound is administered subcutaneously using a 25% HP-ß-CD formulation. Because of the high Caco2 efflux ratio, the oral exposure is very low. Full detail of the in vivo PK data are available from OpnMe.com

Crystal Structure: ternary complex EloBC-VHL : MZ1 : Brd4(BD2). PDB entry code: 5T35 (2)

Negative control: cis MZ1, CAS number: 1797406-72-4, available from Tocris

Primary References: 

  1. Zengerle et al. (2015) Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS. Chem. Biol. 10, 1770.  DOI: 10.1021/acschembio.5b00216; PMID: 26035625
  2. Gadd et al. (2017) Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 13, 514.  DOI: 10.1038/nchembio.2329; PMID: 28288108
  3. Chan et al. (2018) Impact of Target Warhead and Linkage Vector on Inducing Protein Degradation: Comparison of Bromodomain and Extra-Terminal (BET) Degraders Derived From Triazolodiazepine (JQ1) and Tetrahydroquinoline (I-BET726) BET Inhibitor Scaffolds. J. Med. Chem. 61, 504.  DOI: 10.1021/acs.jmedchem.6b01912; PMID: 28595007
  4. Roy et al. (2019) SPR-Measured Dissociation Kinetics of PROTAC Ternary Complexes Influence Target Degradation Rate. ACS Chem. Biol. 14, 361. DOI: 10.1021/acschembio.9b00092; PMID: 30721025

 

Articles that have used MZ1:

  1. 2017 Fernandez-Alonso EMBO reports http://dx.doi.org/10.15252/embr.201643534
  2. 2017 Gadd Nat Chem Biol http://dx.doi.org/10.1038/nchembio.2329
  3. 2017 Chan J Med Chem http://dx.doi.org/10.1021/acs.jmedchem.6b01912
  4. 2017 Wurz J Med Chem http://dx.doi.org/10.1021/acs.jmedchem.6b01781
  5. 2018 Sansam Genes & Dev http://dx.doi.org/10.1101/gad.306464.117
  6. 2018 Leonard Cancer Research http://dx.doi.org/10.1158/0008-5472.CAN-18-0459
  7. 2018 Nowak Nat Chem Biol https://doi.org/10.1038/s41589-018-0055-y
  8. 2018 Testa J Am Chem Soc http://dx.doi.org/10.1021/jacs.8b05807
  9. 2018 Riching ACS Chem Biol http://dx.doi.org/10.1021/acschembio.8b00692
  10. 2018 Aresu Haematologica http://dx.doi.org/10.3324/haematol.2018.207027
  11. 2018 Jensen Front Immunol https://dx.doi.org/10.3389%2Ffimmu.2018.02697
  12. 2019 Roy ACS Chem Biol http://dx.doi.org/10.1021/acschembio.9b00092
  13. 2018 Spradlin Nat Chem Biol http://dx.doi.org/10.1038/s41589-019-0304-8
  14. 2018 Ward ACS Chem Biol http://dx.doi.org/10.1021/acschembio.8b01083
  15. 2019 Piya J Clin Invest https://doi.org/10.1172/JCI120654
  16. 2019 Tsujikawa Clin Epigenetics https://doi.org/10.1186/s13148-019-0696-z
  17. 2019 Lim Haematologica https://doi.org/10.3324/haematol.2018.201483
  18. 2019 Andrieu Cancer Lett https://doi.org/10.1016/j.canlet.2019.08.013
  19. 2019 Noblejas-López J Exp Clin Cancer Res https://doi.org/10.1186/s13046-019-1387-5
  20. 2019 Ottis ACS Chem Biol http://dx.doi.org/10.1021/acschembio.9b00525
  21. 2019 Pillow ChemMedChem https://doi.org/10.1002/cmdc.201900497
  22. 2019 Otto Neoplasia https://doi.org/10.1016/j.neo.2019.10.003
  23. 2019 Shafran Mol Cancer Res https://doi.org/10.1158/1541-7786.mcr-18-1279
  24. 2020 Jiang Gastroenterology https://doi.org/10.1053/j.gastro.2020.06.050
  25. 2020 Kaji Sci Reports https://doi.org/10.1038/s41598-020-59966-5
  26. 2020 Dubois Mol Syst Biol http://doi.org/10.15252/msb.20199156
  27. 2020 Testa Angew Chem Intl Ed https://doi.org/10.1002/anie.201914396
  28. 2020 Foley ACS Chem Biol https://doi.org/10.1021/acschembio.9b00972
  29. 2020 Rosencrance Mol Cell https://doi.org/10.1016/j.molcel.2020.03.018
  30. 2020 Kounde Chem Commun https://doi.org/10.1039/D0CC00523A
  31. 2020 Ermondi Drug Discov Today https://doi.org/10.1016/j.drudis.2020.06.015
  32. 2020 Beveridge ACS Cent Sci https://doi.org/10.1021/acscentsci.0c00049
  33. 2020 Shafran Prostate Cancer Prostatic Dis https://doi.org/10.1038/s41391-020-0246-y
  34. 2020 Klein ACS Med Chem Lett https://doi.org/10.1021/acsmedchemlett.0c00265
  35. 2020 Cimas Pharmaceutics https://doi.org/10.3390/pharmaceutics12100986
  36. 2020 Lin Bioconjugate Chem https://doi.org/10.1021/acs.bioconjchem.0c00507
  37. 2020 Li Front Oncol https://doi.org/10.3389/fonc.2020.574525
  38. 2021 Shirasaki Cell Reports https://doi.org/10.1016/j.celrep.2020.108532
  39. 2021 Alpsoy Cancer Res https://doi.org/10.1158/0008-5472.CAN-20-1417
  40. 2021 Kaiho-Soma Mol Cell https://doi.org/10.1016/j.molcel.2021.01.023
  41. 2021 Dragovich J Med Chem https://doi.org/10.1021/acs.jmedchem.0c01845
  42. 2021 Dragovich J Med Chem https://doi.org/10.1021/acs.jmedchem.0c01846
  43. 2021 Wang Cell Death Differ https://doi.org/10.1038/s41418-021-00751-w
  44. 2021 Noblejas-López J Exp Clin Cancer Res https://doi.org/10.1186/s13046-021-01907-9
  45. 2021 Pietrobono Oncogene https://doi.org/10.1038/s41388-021-01783-9
  46. 2021 Song Cell Chem Biol https://doi.org/10.1016/j.chembiol.2021.05.005
  47. 2021 Wang Nat Commun https://doi.org/10.1038/s41467-021-24687-4
  48. 2021 Massafra J Immunol https://doi.org/10.4049/jimmunol.2000252
  49. 2021 Bhola Head & Neck https://doi.org/10.1002/hed.26827
  50. 2021 Castro RSC Med Chem https://doi.org/10.1039/D1MD00215E
  51. 2021 Tong Oncogene https://doi.org/10.1038/s41388-021-02041-8
  52. 2021 Bond J Med Chem https://doi.org/10.1021/acs.jmedchem.1c01532
  56. 2021 Jafari Science Signal. https://doi.org/10.1126/scisignal.abj2807
  59. 2021 Tarantelli Explor. Target Antitumor Ther. https://doi.org/10.37349/etat.2021.00065
  60. 2022 Müller Clin Epigenet https://doi.org/10.1186/s13148-021-01223-1
  61. 2022 Weerakoon J Chem Inf Model https://doi.org/10.1021/acs.jcim.1c01036
  62. 2022 Luo iScience https://doi.org/10.1016/j.isci.2022.103985
  63. 2023 Hanzl Nat Chem Biol https://doi.org/10.1038/s41589-022-01177-2; 2022 BioRxiv https://doi.org/10.1101/2022.04.14.488316
  64. 2022 García Jiménez J Med Chem https://doi.org/10.1021/acs.jmedchem.2c00201
  65. 2022 Trapotsi ACS Chem Biol https://doi.org/10.1021/acschembio.2c00076
  66. 2022 Mason BioRxiv https://doi.org/10.1101/2022.10.13.512184
  67. 2022 Bhela J Med Chem https://doi.org/10.1021/acs.jmedchem.2c01218
  68. 2023 Toriki ACS Cent Sci https://doi.org/10.1021/acscentsci.2c01317; 2022 BioRxiv https://doi.org/10.1101/2022.11.04.512693
  69. 2022 Lou Science https://doi.org/10.1126/science.abl5829
  70. 2023 Bashore Nat Chem Biol https://doi.org/10.1038/s41589-022-01218-w
  71. 2023 Shergalis ACS Chem Biol https://doi.org/10.1021/acschembio.2c00747
  72. 2023 Hsia BioRxiv https://doi.org/10.1101/2023.02.14.528511
  73. 2023 Li BioRxiv https://doi.org/10.1101/2023.02.14.528208
  74. 2023 Singh Sci Adv https://doi.org/10.1126/sciadv.ade3876
  75. 2023 Steinebach ChemRxiv https://doi.org/10.26434/chemrxiv-2023-zshqp
  76. 2023 Bordi Digital Discovery https://doi.org/10.1039/D3DD00027C
  77. 2023 Tong Nature https://doi.org/10.1038/s41586-023-06091-8
  78. 2023 Bagka Nat Commun https://doi.org/10.1038/s41467-023-39657-1
  79. 2023 Plesniak ChemRxiv https://doi.org/10.26434/chemrxiv-2023-dz9l7
  80. 2023 Hales Chemistry https://doi.org/10.1002/chem.202301975

More information

More information on our chemical probes can be found from the Chemical Probes portal, and from commercial vendors such as Tocris Bio-Techne.

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