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MZ1 | Degrader (PROTAC) of BRD4, BRD3, BRD2
RATINGS:
Cellular Use: (5 reviews)

In Model Organisms: (0 reviews)
Probe Summary
Selectivity
Potency
In Vivo
Control Compounds
Chemical Information
References
Vendors
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Probe Summary

Targets Biochemical/Biophysical Potency Cellular Potency
BRD4
  • Kd:39 nM (BD1), 15 nM (BD2)
  • DC50:5 nM
  • Dmax:98/100%
BRD3
  • Kd:21nM (BD1), 13 nM2 (BD2)
  • DC50:100 nM
  • EC50:50 nM
  • Dmax:100%
BRD2
  • Kd:62 nM (BD1), 60 nM (BD2)
  • DC50:40 nM
  • Dmax:98%
  • EC50:50 nM
Degrader (PROTAC)
100-250 nM

Selectivity

In Vitro Selectivity Assessment

Potency: KD - BRD2(BD1) 307 nM, (BD2) 228 nM , BRD3(BD1) 119 nM, (BD2) 115 nM, VBC 149 nM

Selectivity Assessment Description:
SafetyScreen44™
In Cell Selectivity Assessment

Potency: DC50 - BRD2 and BRD3, 70 nM

Potency Assay Off-Target:
Western blot
Selectivity Assessment Description:
Not done

Potency
Cellular
In Vitro

BRD4

Mode of Action: Degrader (PROTAC)

Structure-Activity-Relationship data available? Yes

DOI Reference: 10.1021/acschembio.5b00216

BRD3

Mode of Action: Degrader (PROTAC)

Structure-Activity-Relationship data available? Yes

DOI Reference: 10.1038/nchembio.2329

BRD2

Mode of Action: Degrader (PROTAC)

Structure-Activity-Relationship data available? Yes

DOI Reference: 10.1038/nchembio.2329

In Vivo Validations

Rat
Dose: 5 mg/Kg
Route of delivery: Intravenous
Plasma half life: 1.52 h
Systemic clearance: 156% QH
Volume of Distribution at Steady-State: 4.05 L/Kg

DOI Reference: 10.1021/acschembio.5b00216

Dose: 5 mg/Kg
Route of delivery: Subcutaneous
Plasma half life: 5.13 h
Cmax: 163 nM
Tmax: 2 h
Area Under the Curve:: 1300 nM*h

DOI Reference: 10.1021/acschembio.5b00216

Mouse
Dose: 5 mg/Kg
Route of delivery: Intravenous
Plasma half life: 1.04 h
Systemic clearance: 20.7% QH
Volume of Distribution at Steady-State: 0.38 L/Kg

DOI Reference: 10.1021/acschembio.5b00216

Dose: 5 mg/Kg
Route of delivery: Subcutaneous
Plasma half life: 2.95 h
Cmax: 2070 nM
Tmax: 0.5 h
Area Under the Curve:: 3760 nM*h

DOI Reference: 10.1021/acschembio.5b00216

Negative Control Compounds

cisMZ1

Orthogonal Probes def

dBET1
ARV-825
dBET6

Chemical Information

Molecular Formula C49H60ClN9O8S2
SMILEs Cc1ncsc1-c1ccc(CNC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)COCCOCCOCCNC(=O)C[C@@H]2N=C(c3ccc(Cl)cc3)c3c(sc(C)c3C)-n3c(C)nnc32)C(C)(C)C)cc1
InChI InChI=1S/C49H60ClN9O8S2/c1-28-30(3)69-48-41(28)42(33-12-14-35(50)15-13-33)54-37(45-57-56-31(4)59(45)48)23-39(61)51-16-17-65-18-19-66-20-21-67-26-40(62)55-44(49(5,6)7)47(64)58-25-36(60)22-38(58)46(63)52-24-32-8-10-34(11-9-32)43-29(2)53-27-68-43/h8-15,27,36-38,44,60H,16-26H2,1-7H3,(H,51,61)(H,52,63)(H,55,62)/t36-,37+,38+,44-/m1/s1
Molecular weight 1001.37 Da
AlogP 5.596680000000006
HBond acceptors 17
HBond donors 4
Atoms 129

References

Publications

Cross References

Vendors

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Expert Reviews

by SERP
(on 23 Dec 2016 )
Cellular Use Rating
MZ1 is a PROTAC compound, made by conjugating the pan-BET inhibitor JQ1 via a PEG linker to a potent ligand for the VHL E3 ligase. This compound preferentially removes a single member of the BET family,...
by SERP
(on 23 Jan 2017 )
Cellular Use Rating
MZ1 is a compound based on the pan-BET inhibitor JQ1 linked to a ligand for the E3 ubiquitin ligase. In a narrow concentration and time range, MZ1 preferentially leads to degradation of BRD4 over the...
by SERP
(on 10 Apr 2017 )
Cellular Use Rating
A 3D crystal structure of MZ1 bound to both VHL and the second bromodomain of BRD4 was solved and published (Gadd et al. Nat Chem Biol, 13 March 2017, doi:10.1038/nchembio.2329) with thermodynamic binding...
MZ1 exhibits potent cytotoxicity and profound anti-proliferative effects in AML cell lines such as Mv4;11 (pEC50 = 7.6), more potent and with greater Emax than (+)-JQ1 (pEC50 = 6.5).
by SERP
(on 27 Jul 2017 )
Cellular Use Rating
This is a very interesting PROTAC version of JQ1. Because of the preference for BRD4 at 100-250 nM, it would be great to compare cell toxicity between MZ1 and JQ1. Further SAR data for MZ1 and other...
Further SAR data for MZ1 and other analogues with different PEG linkers (MZ4 = PEG2; MZ2 = PEG4) were published (Chan et al. J Med Chem. DOI: 10.1021/acs.jmedchem.6b01912). SAR data include BET protein...
Plasma stability ( In vitro Half life) of MZ1 > 180 min i.e. MZ1 is fully stable in plasma within the assay window (3 h).
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