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A public-private partnership that supports the discovery of new medicines through open access research.
MRK-740 for PRDM9This probe is available from Tocris and Sigma. The negative control is available from Sigma. For any inquiries please contact proberequests@thesgc.org.group newOverview MRK-740 MRK-740-NC A collaboration between MSD and the SGC has resulted in the discovery of MRK-740, a potent inhibitor of PRDM9 with a peptide competitive MOA. MRK-740 inhibits in vitro methylation of H3K4 with IC50 = 85 nM and shows more than 100-fold selectivity over other histone methyltransferases and other non-epigenetic targets. MRK-740 inhibits the methylation of H3K4 in cells with IC50 = 0.8 µM. A control compound, MRK-740-NC, has also been developed which inhibits the in vitro methylation of H3K4 with IC50 > 100 µM. The use of this compound at 3 µM is recommended in cells. Data relating to the discovery of this probe is being prepared for publication. In the meantime, in order to facilitate research by the community we are making this compound available through this website. Properties MRK-740 MRK-740-NC (negative control) Physical and chemical properties for MRK-740 Molecular weight 464.3 Molecular formula C25H32N6O3 IUPAC name 4-(3-(3,5-dimethoxy-phenyl)-1,2,4-oxadiazol-5-yl)-1-methyl-9-(2-methyl-pyridin-4-yl)-1,4,9-triaza-spiro[5.5]undecane MollogP 2.851 PSA 65.67 No. of chiral centres 0 No. of rotatable bonds 7 No. of hydrogen bond acceptors 5 No. of hydrogen bond donors 0 Physical and chemical properties for MRK-740-NC (Negative Control) Molecular weight 449.2 Molecular formula C25H31N5O3 IUPAC name 4-(3-(3,5-dimethoxy-phenyl)-1,2,4-oxadiazol-5-yl)-1-methyl-9-phenyl-1,4,9-triaza-spiro[5.5]undecane MollogP 3.519 PSA 56.81 No. of chiral centres 0 No. of rotatable bonds 5 No. of hydrogen bond acceptors 6 No. of hydrogen bond donors 0 SMILES: MRK-740: Cc1cc(ccn1)N1CCC2(CC1)CN(CCN2C)c1nc(c2cc(cc(c2)OC)OC)no1 MRK-740-NC: CN1CCN(CC12CCN(CC2)c1ccccc1)c1nc(c2cc(cc(c2)OC)OC)no1 InChI: MRK-740: InChI=1S/C25H32N6O3/c1-18-13-20(5-8-26-18)30-9-6-25(7-10-30)17-31(12-11-29(25)2)24-27-23(28-34-24)19-14-21(32-3)16-22(15-19)33-4/h5,8,13-16H,6-7,9-12,17H2,1-4H3 MRK-740-NC: InChI=1S/C25H31N5O3/c1-28-13-14-30(18-25(28)9-11-29(12-10-25)20-7-5-4-6-8-20)24-26-23(27-33-24)19-15-21(31-2)17-22(16-19)32-3/h4-8,15-17H,9-14,18H2,1-3H3 InChIKey: MRK-740: NZYTZRHHBAJPKN-UHFFFAOYSA-N MRK-740-NC: OACWMVMQWRVMAF-UHFFFAOYSA-N Co-crystal structures Please wait whilst the interactive viewer is loaded! Main features 1. Active form of mPRDM9 showing H3 peptide stabilized by C-terminus of SET domain (orange). 2. Overlay with inactive form of hPRDM9 which does not contain SAM or H3 peptide. Note the displacement of the helix (blue) which is stabilized in the active form (orange). 3. Binding of MRK-740 destabilizes the helix in similar manner to that of the apo-form (blue). 4. Overview of MRK-740 bound to mPRDM9 with SAM. 5. Detailed view of MRK-740 binding.