(R)-PFI-2

(R)-PFI-2 A probe for SETD7

This probe is available from Sigma (including its negative control), Tocris (including its negative control) and Cayman Chemical (including its negative control)

  • overview
  • properties
  • selectivity profile
  • cell based assay data
  • references
  • co-crystal structures
overview

A collaboration between the SGC and Pfizer has resulted in the discovery of (R)-PFI-2, a chemical Probe for SETD7.  PFI-2 is a potent inhibitor of SETD7 with IC50 2 nM and 1000-fold selectivity over other methyltransferases and other non-epigenetic targets.  PFI-2 has been shown to bind to SETD7 by ITC (Kd=18nM) and biotinylated PFI-2 interacts with SETD7 in pull-down studies.  Its enantiomer (S)-PFI-2 is 500-fold less active making it an excellent negative control.  Treatment of low-density MEFs with (R)-PFI-2 resulted in higher nuclear YAP levels indicating an effect on the Hippo pathway.

properties


(S)-PFI-2


(R)-PFI-2

Physical and chemical properties for (S)-PFI-2
Molecular weight499.2
Molecular formulaC23H25F4N3O3S
MollogP3.504
PSA70.67
No. of chiral centres1
No. of rotatable bonds8
No. of hydrogen bond acceptors8
No. of hydrogen bond donors2
Physical and chemical properties for (R)-PFI-2
Molecular weight499.2
Molecular formulaC23H25F4N3O3S
MollogP3.504
PSA70.67
No. of chiral centres1
No. of rotatable bonds8
No. of hydrogen bond acceptors8
No. of hydrogen bond donors2
  • SMILES:
  • (S)-PFI-2: C1CCN(C1)C([C@H](Cc1cccc(c1)C(F)(F)F)NS(c1cc2CCNCc2c(c1)F)(=O)=O)=O
  • (R)-PFI-2: C1CCN(C1)C([C@@H](Cc1cccc(c1)C(F)(F)F)NS(c1cc2CCNCc2c(c1)F)(=O)=O)=O
  • InChI:
  • (S)-PFI-2: InChI=1S/C23H25F4N3O3S/c24-20-13-18(12-16-6-7-28-14-19(16)20)34(32,33)29-21(22(31)30-8-1-2-9-30)11-15-4-3-5-17(10-15)23(25,26)27/h3-5,10,12-13,21,28-29H,1-2,6-9,11,14H2/t21-/m0/s1
  • (R)-PFI-2: InChI=1S/C23H25F4N3O3S/c24-20-13-18(12-16-6-7-28-14-19(16)20)34(32,33)29-21(22(31)30-8-1-2-9-30)11-15-4-3-5-17(10-15)23(25,26)27/h3-5,10,12-13,21,28-29H,1-2,6-9,11,14H2/t21-/m1/s1
  • InChIKey:
  • (S)-PFI-2: JCKGSPAAPQRPBW-NRFANRHFSA-N
  • (R)-PFI-2: JCKGSPAAPQRPBW-OAQYLSRUSA-N
selectivity profile

in vitro potency
cell based assay data
references

Barsyte-Lovejoy D, Li F, Oudhoff MJ, Tatlock JH, Dong A, Zeng H, Wu H, Freeman SA, Schapira M, Senisterra GA, Kuznetsova E, Marcellus R, Allali-Hassani A, Kennedy S, Lambert JP, Couzens AL, Aman A, Gingras AC, Al-Awar R, Fish PV, Gerstenberger BS, Roberts L, Benn CL, Grimley RL, Braam MJ, Rossi FM, Sudol M, Brown PJ, Bunnage ME, Owen DR, Zaph C, Vedadi M, Arrowsmith CH. (R)-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells. Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):12853-8. doi: 10.1073/pnas.1407358111. Epub 2014 Aug 18.

pk properties
co-crystal structures

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Main features

  • PFI-2 efficiently exploits the substrate binding site of SETD7.
  • PFI-2 interacts directly with the departing methyl group of SAM.
  • PFI-2 occupies the lysine binding site of SETD7.
synthetic schemes
materials and methods
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