{"id":111,"date":"2023-10-27T11:40:38","date_gmt":"2023-10-27T10:40:38","guid":{"rendered":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/?page_id=111"},"modified":"2026-01-26T14:11:12","modified_gmt":"2026-01-26T14:11:12","slug":"mz1","status":"publish","type":"page","link":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/research\/chemical-probes\/mz1\/","title":{"rendered":"MZ1"},"content":{"rendered":"
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\"BET
\n <\/source><\/source><\/figure>\n

MZ1<\/p>\n

Protein Target(s) Name<\/strong>: BET proteins BRD4, BRD3, BRD2<\/p>\n

Mechanism of Action<\/strong>: PROTAC degrader<\/p>\n

Description<\/strong>: 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<\/em>).<\/p>\n

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

CAS Number<\/strong>:\u00a01797406-69-9<\/a><\/p>\n

In vitro pharmacology*:<\/strong>\u00a0MZ1 reduces BET protein levels in human cells: Brd4 pDC50 | Dmax (%) in HeLa cells (24 h) = 8.6 | 100
\nMZ1 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
\nData from ref. (3<\/em>)<\/p>\n

*DC50: concentration in molar causing 50% reduction of protein level relative to vehicle control treatment.
\nDmax: maximum reduction of protein level relative to vehicle control treatment.
\nEC50: effective concentration in molar causing 50% reduction of cell viability relative to vehicle control treatment.<\/p>\n

Biophysical binding data<\/strong>: ITC binary Kd (Brd4-BD2) = 15 nM;\u00a0ITC 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 =\u00a0-22.2 kcal\/mol.\u00a0Data from ref. (2<\/em>)
\nTernary complex VHL:MZ1:Brd4-BD2 t1\/2 (SPR) = 130 s. FP ternary Kd (VHL, in the presence of Brd4-BD2) = 1.3 nM.\u00a0Data from ref. (4<\/em>)<\/p>\n

In vivo PK data<\/strong>: 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-\u00df-CD formulation. Because of the high Caco2 efflux ratio, the oral exposure is very low. Full detail of the\u00a0in vivo<\/em>\u00a0PK data are available from\u00a0OpnMe.com<\/a><\/p>\n

Crystal Structure<\/strong>:\u00a0ternary complex EloBC-VHL : MZ1 : Brd4(BD2). PDB entry code:\u00a05T35<\/a>\u00a0(2<\/em>)<\/p>\n

Negative control<\/strong>: cis MZ1, CAS number:\u00a01797406-72-4<\/a>, available from\u00a0Tocris<\/a><\/p>\n

<\/div>\n

Primary References:\u00a0<\/strong><\/p>\n

    \n
  1. Zengerle et al. (2015<\/strong>) Selective small molecule induced degradation of the BET bromodomain protein BRD4.\u00a0ACS. Chem. Biol.<\/em>\u00a010<\/em>, 1770.\u00a0 DOI:\u00a010.1021\/acschembio.5b00216<\/a>; PMID:\u00a026035625<\/a><\/li>\n
  2. Gadd et al. (2017<\/strong>) Structural basis of PROTAC cooperative recognition for selective protein degradation.\u00a0Nat. Chem. Biol.<\/em>\u00a013<\/em>, 514.\u00a0 DOI:\u00a010.1038\/nchembio.2329<\/a>; PMID:\u00a028288108<\/a><\/li>\n
  3. Chan et al. (2018<\/strong>)\u00a0Impact 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.\u00a0J. Med. Chem.<\/em>\u00a061<\/em>, 504.\u00a0 DOI:\u00a010.1021\/acs.jmedchem.6b01912<\/a>; PMID:\u00a028595007<\/a><\/li>\n
  4. Roy et al. (2019<\/strong>) SPR-Measured Dissociation Kinetics of PROTAC Ternary Complexes Influence Target Degradation Rate.\u00a0ACS Chem. Biol.<\/em>\u00a014<\/em>, 361. DOI:\u00a010.1021\/acschembio.9b00092<\/a>; PMID:\u00a030721025<\/a><\/li>\n<\/ol>\n

    \u00a0<\/p>\n

    Articles that have used MZ1<\/strong>:<\/p>\n

      \n
    1. 2017 Fernandez-Alonso EMBO reports\u00a0http:\/\/dx.doi.org\/10.15252\/embr.201643534<\/a><\/li>\n
    2. 2017 Gadd Nat Chem Biol\u00a0http:\/\/dx.doi.org\/10.1038\/nchembio.2329<\/a><\/li>\n
    3. 2017 Chan J Med Chem\u00a0http:\/\/dx.doi.org\/10.1021\/acs.jmedchem.6b01912<\/a><\/li>\n
    4. 2017 Wurz J Med Chem\u00a0http:\/\/dx.doi.org\/10.1021\/acs.jmedchem.6b01781<\/a><\/li>\n
    5. 2018 Sansam Genes & Dev\u00a0http:\/\/dx.doi.org\/10.1101\/gad.306464.117<\/a><\/li>\n
    6. 2018 Leonard Cancer Research\u00a0http:\/\/dx.doi.org\/10.1158\/0008-5472.CAN-18-0459<\/a><\/li>\n
    7. 2018 Nowak Nat Chem Biol\u00a0https:\/\/doi.org\/10.1038\/s41589-018-0055-y<\/a><\/li>\n
    8. 2018 Testa J Am Chem Soc\u00a0http:\/\/dx.doi.org\/10.1021\/jacs.8b05807<\/a><\/li>\n
    9. 2018 Riching ACS Chem Biol\u00a0http:\/\/dx.doi.org\/10.1021\/acschembio.8b00692<\/a><\/li>\n
    10. 2018 Aresu Haematologica\u00a0http:\/\/dx.doi.org\/10.3324\/haematol.2018.207027<\/a><\/li>\n
    11. 2018 Jensen Front Immunol\u00a0https:\/\/dx.doi.org\/10.3389%2Ffimmu.2018.02697<\/a><\/li>\n
    12. 2019 Roy ACS Chem Biol\u00a0http:\/\/dx.doi.org\/10.1021\/acschembio.9b00092<\/a><\/li>\n
    13. 2018 Spradlin Nat Chem Biol http:\/\/dx.doi.org\/10.1038\/s41589-019-0304-8<\/a><\/li>\n
    14. 2018 Ward ACS Chem Biol\u00a0http:\/\/dx.doi.org\/10.1021\/acschembio.8b01083<\/a><\/li>\n
    15. 2019 Piya J Clin Invest\u00a0https:\/\/doi.org\/10.1172\/JCI120654<\/a><\/li>\n
    16. 2019 Tsujikawa Clin Epigenetics\u00a0https:\/\/doi.org\/10.1186\/s13148-019-0696-z<\/a><\/li>\n
    17. 2019 Lim Haematologica\u00a0https:\/\/doi.org\/10.3324\/haematol.2018.201483<\/a><\/li>\n
    18. 2019 Andrieu Cancer Lett\u00a0https:\/\/doi.org\/10.1016\/j.canlet.2019.08.013<\/a><\/li>\n
    19. 2019 Noblejas-L\u00f3pez J Exp Clin Cancer Res\u00a0https:\/\/doi.org\/10.1186\/s13046-019-1387-5<\/a><\/li>\n
    20. 2019 Ottis ACS Chem Biol\u00a0http:\/\/dx.doi.org\/10.1021\/acschembio.9b00525<\/a><\/li>\n
    21. 2019 Pillow ChemMedChem\u00a0https:\/\/doi.org\/10.1002\/cmdc.201900497<\/a><\/li>\n
    22. 2019 Otto Neoplasia\u00a0https:\/\/doi.org\/10.1016\/j.neo.2019.10.003<\/a><\/li>\n
    23. 2019 Shafran Mol Cancer Res https:\/\/doi.org\/10.1158\/1541-7786.mcr-18-1279<\/a><\/li>\n
    24. 2020 Jiang Gastroenterology https:\/\/doi.org\/10.1053\/j.gastro.2020.06.050<\/a><\/li>\n
    25. 2020 Kaji Sci Reports\u00a0https:\/\/doi.org\/10.1038\/s41598-020-59966-5<\/a><\/li>\n
    26. 2020 Dubois Mol Syst Biol\u00a0http:\/\/doi.org\/10.15252\/msb.20199156<\/a><\/li>\n
    27. 2020 Testa Angew Chem Intl Ed\u00a0https:\/\/doi.org\/10.1002\/anie.201914396<\/a><\/li>\n
    28. 2020 Foley ACS Chem Biol\u00a0https:\/\/doi.org\/10.1021\/acschembio.9b00972<\/a><\/li>\n
    29. 2020 Rosencrance Mol Cell\u00a0https:\/\/doi.org\/10.1016\/j.molcel.2020.03.018<\/a><\/li>\n
    30. 2020 Kounde Chem Commun\u00a0https:\/\/doi.org\/10.1039\/D0CC00523A<\/a><\/li>\n
    31. 2020 Ermondi Drug Discov Today\u00a0https:\/\/doi.org\/10.1016\/j.drudis.2020.06.015<\/a><\/li>\n
    32. 2020 Beveridge ACS Cent Sci\u00a0https:\/\/doi.org\/10.1021\/acscentsci.0c00049<\/a><\/li>\n
    33. 2020\u00a0Shafran Prostate Cancer Prostatic Dis\u00a0https:\/\/doi.org\/10.1038\/s41391-020-0246-y<\/a><\/li>\n
    34. 2020 Klein ACS Med Chem Lett\u00a0https:\/\/doi.org\/10.1021\/acsmedchemlett.0c00265<\/a><\/li>\n
    35. 2020 Cimas Pharmaceutics https:\/\/doi.org\/10.3390\/pharmaceutics12100986<\/a><\/li>\n
    36. 2020 Lin Bioconjugate Chem https:\/\/doi.org\/10.1021\/acs.bioconjchem.0c00507<\/a><\/li>\n
    37. 2020\u00a0Li Front Oncol\u00a0https:\/\/doi.org\/10.3389\/fonc.2020.574525<\/a><\/li>\n
    38. 2021 Shirasaki Cell Reports\u00a0https:\/\/doi.org\/10.1016\/j.celrep.2020.108532<\/a><\/li>\n
    39. 2021\u00a0Alpsoy Cancer Res\u00a0https:\/\/doi.org\/10.1158\/0008-5472.CAN-20-1417<\/a><\/li>\n
    40. 2021 Kaiho-Soma Mol Cell https:\/\/doi.org\/10.1016\/j.molcel.2021.01.023<\/a><\/li>\n
    41. 2021 Dragovich J Med Chem https:\/\/doi.org\/10.1021\/acs.jmedchem.0c01845<\/a><\/li>\n
    42. 2021 Dragovich J Med Chem https:\/\/doi.org\/10.1021\/acs.jmedchem.0c01846<\/a><\/li>\n
    43. 2021 Wang Cell Death Differ https:\/\/doi.org\/10.1038\/s41418-021-00751-w<\/a><\/li>\n
    44. 2021 Noblejas-L\u00f3pez J Exp Clin Cancer Res https:\/\/doi.org\/10.1186\/s13046-021-01907-9<\/a><\/li>\n
    45. 2021 Pietrobono Oncogene\u00a0https:\/\/doi.org\/10.1038\/s41388-021-01783-9<\/a><\/li>\n
    46. 2021 Song Cell Chem Biol\u00a0https:\/\/doi.org\/10.1016\/j.chembiol.2021.05.005<\/a><\/li>\n
    47. 2021 Wang Nat Commun\u00a0https:\/\/doi.org\/10.1038\/s41467-021-24687-4<\/a><\/li>\n
    48. 2021 Massafra J Immunol\u00a0https:\/\/doi.org\/10.4049\/jimmunol.2000252<\/a><\/li>\n
    49. 2021 Bhola Head & Neck\u00a0https:\/\/doi.org\/10.1002\/hed.26827<\/a><\/li>\n
    50. 2021 Castro RSC Med Chem\u00a0https:\/\/doi.org\/10.1039\/D1MD00215E<\/a><\/li>\n
    51. 2021 Tong Oncogene\u00a0https:\/\/doi.org\/10.1038\/s41388-021-02041-8<\/a><\/li>\n
    52. 2021 Bond J Med Chem\u00a0https:\/\/doi.org\/10.1021\/acs.jmedchem.1c01532<\/a><\/li>\n
    53. \n
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    61. \n
    62. 2022 Luo iScience\u00a0https:\/\/doi.org\/10.1016\/j.isci.2022.103985<\/a><\/li>\n
    63. 2023 Hanzl Nat Chem Biol\u00a0https:\/\/doi.org\/10.1038\/s41589-022-01177-2;<\/a>\u00a02022 BioRxiv\u00a0https:\/\/doi.org\/10.1101\/2022.04.14.488316<\/a><\/li>\n
    64. 2022\u00a0Garc\u00eda Jim\u00e9nez J Med Chem\u00a0https:\/\/doi.org\/10.1021\/acs.jmedchem.2c00201<\/a><\/li>\n
    65. 2022 Trapotsi ACS Chem Biol\u00a0https:\/\/doi.org\/10.1021\/acschembio.2c00076<\/a><\/li>\n
    66. 2022 Mason BioRxiv\u00a0https:\/\/doi.org\/10.1101\/2022.10.13.512184<\/a><\/li>\n
    67. 2022 Bhela J Med Chem\u00a0https:\/\/doi.org\/10.1021\/acs.jmedchem.2c01218<\/a><\/li>\n
    68. 2023 Toriki ACS Cent Sci\u00a0https:\/\/doi.org\/10.1021\/acscentsci.2c01317;<\/a>\u00a02022 BioRxiv\u00a0https:\/\/doi.org\/10.1101\/2022.11.04.512693<\/a><\/li>\n
    69. 2022 Lou Science\u00a0https:\/\/doi.org\/10.1126\/science.abl5829<\/a><\/li>\n
    70. 2023 Bashore Nat Chem Biol\u00a0https:\/\/doi.org\/10.1038\/s41589-022-01218-w<\/a><\/li>\n
    71. 2023 Shergalis ACS Chem Biol\u00a0https:\/\/doi.org\/10.1021\/acschembio.2c00747<\/a><\/li>\n
    72. 2023 Hsia BioRxiv\u00a0https:\/\/doi.org\/10.1101\/2023.02.14.528511<\/a><\/li>\n
    73. 2023 Li BioRxiv\u00a0https:\/\/doi.org\/10.1101\/2023.02.14.528208<\/a><\/li>\n
    74. 2023 Singh Sci Adv\u00a0https:\/\/doi.org\/10.1126\/sciadv.ade3876<\/a><\/li>\n
    75. 2023 Steinebach ChemRxiv\u00a0https:\/\/doi.org\/10.26434\/chemrxiv-2023-zshqp<\/a><\/li>\n
    76. 2023 Bordi Digital Discovery\u00a0https:\/\/doi.org\/10.1039\/D3DD00027C<\/a><\/li>\n
    77. 2023 Tong Nature\u00a0https:\/\/doi.org\/10.1038\/s41586-023-06091-8<\/a><\/li>\n
    78. 2023 Bagka Nat Commun\u00a0https:\/\/doi.org\/10.1038\/s41467-023-39657-1<\/a><\/li>\n
    79. 2023 Plesniak ChemRxiv\u00a0https:\/\/doi.org\/10.26434\/chemrxiv-2023-dz9l7<\/a><\/li>\n
    80. 2023 Hales Chemistry\u00a0https:\/\/doi.org\/10.1002\/chem.202301975<\/a><\/li>\n<\/ol>\n

      More information<\/h2>\n

      More information on our chemical probes can be found from the\u00a0Chemical Probes portal<\/a>, and from commercial vendors such as\u00a0Tocris Bio-Techne<\/a>.<\/p>\n

      Related links<\/h3>\n