Protein Target(s) Name: BET proteins BRD4, BRD3, BRD2
Mechanism of Action: PROTAC degrader
Description: VH032 (VHL) based and IBET-726 based PROTAC that degrades BET proteins in cells. MZP-54 exhibits preferential degradation of BRD3 and BRD4 at nM concentrations over BRD2 (1).
Chemical Name: (2S,4R)-1-((S)-1-(4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-15-(tert-butyl)-1,13-dioxo-5,8,11-trioxa-2,14-diazahexadecan-16-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
CAS Number: 2010159-47-2
In vitro pharmacology*: MZP-54 reduces BET protein levels in human cells: Brd4 pDC50 | Dmax (%) in HeLa cells (24 h) = 8.1 | 98; Brd3 pDC50 | Dmax (%) in HeLa cells (24 h) = 7.3 | 91
MZP-54 shows antiproliferative and Myc-suppression activity in AML MV4;11 and HL60 cells: pEC50 in MV4;11 | HL-60 cells (48 h) = 7.3 | 6.6
Data from ref. (1)
*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: Binary Kd (Brd4-BD2) = 4 nM; Binary Kd (VHL) = 105 nM; Ternary Kd (VHL, in the presence of Brd4-BD2) = 230 nM; cooperativity (alpha) = 0.5
Data from ref. (1)
In vivo PK data: not available
Crystal Structure: not available
Negative control: not available
- 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
Articles that have used MZP-54:
- 2018 Chan J Med Chem http://dx.doi.org/10.1021/acs.jmedchem.6b01912
- 2021 Castro RSC Med Chem https://doi.org/10.1039/D1MD00215E
- 2021 Weng J Med Chem https://doi.org/10.1021/acs.jmedchem.1c01576
- 2022 García Jiménez J Med Chem https://doi.org/10.1021/acs.jmedchem.2c00201