MZ1

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, BRD4, over BRD2 and BRD3 at low concentrations. The downstream gene expression pattern resulting from treatment with MZ1 is similar to JQ1 inhibition for BRD4-dependent genes MYC, P21, and AREG but not for FAS, FGFR1, and TYRO3. Compound was not tested in an in vivo setting

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 BET proteins BRD2 and BRD3. The differential effect to the parent compound JQ1 is reflected in the gene expression pattern upon treatment of HeLa cells with either compound, which reveals differences in the expression of some genes like TYRO3 or FGFR1.

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 data of ternary complex formation by isothermal titration calorimetry. The RSCB PDB entry code of the structure is 53T5. 

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).

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 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 degradation profiles in HeLa cells (pDC50s and Dmax); cellular cytotoxicity profiles in AML lines Mv4;11 and HL-60 (pEC50s, and maximal response to baseline level at the higher concentrations: Emax); and Brd4 and c-Myc percent depletion in AML cell lines. Application of MZ1 as a chemical probe to dissect individual distinct functions of BRD2 and BRD4 in pluripotent stem cells (PSCs) to coordinate pluripotent exit is reported (Fernandez-Alonso, EMBO Rep. DOI 10.15252/embr.20164353)

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 degradation profiles in HeLa cells (pDC50s and Dmax); cellular cytotoxicity profiles in AML lines Mv4;11 and HL-60 (pEC50s, and maximal response to baseline level at the higher concentrations: Emax); and Brd4 and c-Myc percent depletion in AML cell lines. Application of MZ1 as a chemical probe to dissect individual distinct functions of BRD2 and BRD4 in pluripotent stem cells (PSCs) to coordinate pluripotent exit is reported (Fernandez-Alonso, EMBO Rep. DOI 10.15252/embr.201643534)

Plasma stability ( In vitro Half life) of MZ1 > 180 min i.e. MZ1 is fully stable in plasma within the assay window (3 h).