PFI-5

PFI-5 A potent inhibitor of SMYD2 with mixed MOA

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  • overview
  • properties
  • co-crystal structures
overview

A collaboration between Pfizer and the SGC has resulted in the discovery of PFI-5, a potent inhibitor of SMYD2 with mixed MOA. PFI-5 has a unique chemotype relative to the current SMYD2 chemical probes LLY-507 and BAY-598. PFI-5 inhibits in vitro methylation of p53K370 with IC50 = 9 nM and has more than 100-fold selectivity over other histone methyltransferases and other non-epigenetic targets. PFI-5 inhibits the methylation of p53K370 in cells with IC50 = 0.9 µM.  A control compound, PFI-5N, has also been developed which inhibits the in vitro methylation of p53K370 with IC50 > 10 micromolar.

properties


PFI-5


PFI-5N
(negative control)

Physical and chemical properties for PFI-5
Molecular weight561.3
Molecular formulaC29H39N7O.C2H4O2
IUPAC name(3-(2-amino-4-methyl-3,7,9-triaza-bicyclo[4.3.0]nona-1(6),2,4,8-tetraen-7-yl)-3-methyl-azetidin-1-yl)-(1-((1-(cyclohept-2-enyl)-piperidin-4-yl)-methyl)-1H-pyrrol-3-yl)-methanone;acetic acid
MollogP2.93
PSA93.76
No. of chiral centres1
No. of rotatable bonds6
No. of hydrogen bond acceptors8
No. of hydrogen bond donors3
Physical and chemical properties for PFI-5N (Negative Control)
Molecular weight575.4
Molecular formulaC30H41N7O.C2H4O2
IUPAC name(3-(2-amino-4-methyl-3,7,9-triaza-bicyclo[4.3.0]nona-1(6),2,4,8-tetraen-7-yl)-3-methyl-azetidin-1-yl)-(1-((1-(cyclohept-2-enyl)-piperidin-4-yl)-methyl)-2-methyl-1H-pyrrol-3-yl)-methanone;acetic acid
MollogP3.191
PSA63.57
No. of chiral centres1
No. of rotatable bonds6
No. of hydrogen bond acceptors8
No. of hydrogen bond donors3
  • SMILES:
  • PFI-5: [H][C@]1(CCCCC=C1)N1CCC(CC1)Cn1ccc(c1)C(N1CC(C)(C1)n1cnc2c(N)nc(C)cc12)=O.CC(O)=O
  • PFI-5N: [H][C@@]1(CCCCC=C1)N1CCC(CC1)Cn1ccc(C(N2CC(C)(C2)n2cnc3c(N)nc(C)cc23)=O)c1C.CC(O)=O
  • InChI:
  • PFI-5: InChI=1S/C29H39N7O.C2H4O2/c1-21-15-25-26(27(30)32-21)31-20-36(25)29(2)18-35(19-29)28(37)23-11-12-33(17-23)16-22-9-13-34(14-10-22)24-7-5-3-4-6-8-24;1-2(3)4/h5,7,11-12,15,17,20,22,24H,3-4,6,8-10,13-14,16,18-19H2,1-2H3,(H2,30,32);1H3,(H,3,4)/t24-;/m0./s1
  • PFI-5N: InChI=1S/C30H41N7O.C2H4O2/c1-21-16-26-27(28(31)33-21)32-20-37(26)30(3)18-36(19-30)29(38)25-12-15-35(22(25)2)17-23-10-13-34(14-11-23)24-8-6-4-5-7-9-24;1-2(3)4/h6,8,12,15-16,20,23-24H,4-5,7,9-11,13-14,17-19H2,1-3H3,(H2,31,33);1H3,(H,3,4)/t24-;/m1./s1
  • InChIKey:
  • PFI-5: TZMQFZRIXDLOHW-JIDHJSLPSA-N
  • PFI-5N: ULGRWRIEYNNUIE-GJFSDDNBSA-N
selectivity profile
in vitro potency
cell based assay data
references
pk properties
co-crystal structures

Main features

  • SMYD2 structure with peptide substrate and SAM
  • Structures of BAY-598 and AZ-505 showing these bind in the substrate pocket
  • PFI-5 occupies both the SAM and peptide pockets
  • Overall view of PFI-5 binding to SMYD2
  • Key interactions of PFI-5 with SMYD2
synthetic schemes
materials and methods
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