GSK591

GSK591 A chemical probe for PRMT5

This probe is available from Cayman Chemical, Tocris and Sigma.

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

Protein arginine methyltransferases (PRMTs) play a crucial role in a variety of biological processes [1]. Overexpression of PRMTs has been implicated in various human diseases including cancer [2-4]. To date, nine PRMTs have been identified and they are grouped into three categories: types I, II and III. Type II PRMTs, 5 and 9, catalyze symmetric dimethylation of arginine residues, however, PRMT5 is the predominant enzyme for this process. PRMT5 interacts with a number of binding partners that influence its substrate specificity. In particular, MEP50, a member of the WD40 family of proteins, is required for PRMT5 methyltransferase activity.

PRMT5 is reported to have a role in mantle cell lymphoma (MCL) as evidenced by its upregulation in patient samples [5,6]. Consequently, a chemical probe of PRMT5 would be a very useful tool for testing biological and therapeutic hypotheses. The first chemical probe of PRMT5 was co-developed by Epizyme and GlaxoSmithKline (GSK) [7]. An analog of this compound, EPZ015866/GSK3203591 [8], has been kindly donated to the SGC for distribution as GSK591. In an in vitro biochemical assay, GSK591 potently inhibits the PRMT5/MEP50 complex from methylating (histone) H4 with IC50 = 11 nM. In Z-138 cells, GSK591 inhibits the symmetric arginine methylation of SmD3 with EC50 = 56 nM. Further, GSK591 is selective for PRMT5 (up to 50 micromolar) relative to a panel of methyltransferases. 

A control compound, SGC2096, that is inactive up to 10 micromolar is also available from the SGC.

In addition, a biotinylated inhibitor, SGC3185 is available

In Vitro potency

Radioactivity assay using H4 (1-15) as substrate

properties


GSK591


SGC2096

Physical and chemical properties for GSK591
Molecular weight380.2
Molecular formulaC22H28N4O2
IUPAC name(3-(3-aza-bicyclo[4.4.0]deca-1(10),6,8-trien-3-yl)-2-hydroxy-propylamino)-(2-cyclobutylamino-pyridin-4-yl)-methanone
MollogP2.311
PSA64.84
No. of chiral centres1
No. of rotatable bonds8
No. of hydrogen bond acceptors5
No. of hydrogen bond donors3
Physical and chemical properties for SGC2096
Molecular weight332.2
Molecular formulaC18H28N4O2
IUPAC name(2-cyclobutylamino-pyridin-4-yl)-(2-hydroxy-3-(piperidin-1-yl)-propylamino)-methanone
MollogP1.991
PSA65.18
No. of chiral centres1
No. of rotatable bonds8
No. of hydrogen bond acceptors5
No. of hydrogen bond donors3
  • SMILES:
  • GSK591: C1CC(C1)Nc1cc(ccn1)C(NC[C@@H](CN1CCc2ccccc2C1)O)=O
  • SGC2096: C1CCN(CC1)C[C@H](CNC(c1ccnc(c1)NC1CCC1)=O)O
  • InChI:
  • GSK591: InChI=1S/C22H28N4O2/c27-20(15-26-11-9-16-4-1-2-5-18(16)14-26)13-24-22(28)17-8-10-23-21(12-17)25-19-6-3-7-19/h1-2,4-5,8,10,12,19-20,27H,3,6-7,9,11,13-15H2,(H,23,25)(H,24,28)/t20-/m0/s1
  • SGC2096: InChI=1S/C18H28N4O2/c23-16(13-22-9-2-1-3-10-22)12-20-18(24)14-7-8-19-17(11-14)21-15-5-4-6-15/h7-8,11,15-16,23H,1-6,9-10,12-13H2,(H,19,21)(H,20,24)/t16-/m0/s1
  • InChIKey:
  • GSK591: TWKYXZSXXXKKJU-FQEVSTJZSA-N
  • SGC2096: DCHQEWPVLGTADW-INIZCTEOSA-N


SGC3185

Physical and chemical properties for GSK3185
Molecular weight854.4
Molecular formulaC42H62N8O9S
IUPAC name6-(5-(2-(2-(2-(2-(3-(3-(4-((3-(3-aza-bicyclo[4.4.0]deca-1(10),6,8-trien-3-yl)-2-hydroxy-propylamino)-formyl)-pyridin-2-ylamino)-azetidin-1-yl)-3-oxo-propoxy)-ethoxy)-ethoxy)-ethoxy)-ethylamino)-5-oxo-pentyl)-7-thia-2,4-diaza-bicyclo[3.3.0]octan-3-one
MollogP1.341
PSA175.1
No. of chiral centres4
No. of rotatable bonds30
No. of hydrogen bond acceptors16
No. of hydrogen bond donors6

SMILES: [H][C@@]12[C@H](CCCCC(NCCOCCOCCOCCOCCC(N3CC(C3)Nc3cc(ccn3)C(NC[C@@H](CN3CCc4ccccc4C3)O)=O)=O)=O)SC[C@]1([H])NC(N2)=O

InChI: InChI=1S/C42H62N8O9S/c51-34(28-49-14-10-30-5-1-2-6-32(30)25-49)24-45-41(54)31-9-12-43-37(23-31)46-33-26-50(27-33)39(53)11-15-56-17-19-58-21-22-59-20-18-57-16-13-44-38(52)8-4-3-7-36-40-35(29-60-36)47-42(55)48-40/h1-2,5-6,9,12,23,33-36,40,51H,3-4,7-8,10-11,13-22,24-29H2,(H,43,46)(H,44,52)(H,45,54)(H2,47,48,55)/t34-,35-,36-,40-/m0/s1

InChIKey: PZIWNLNYZRZJCY-VNLYVSNMSA-N

selectivity profile

in vitro potency
cell based assay data

Dose-dependant decrease in SDMA in Z-138 cells

references

References

  1. Bedford M T and Clarke SG (2009) Protein Arginine Methylation in Mammals: Who, What, and Why, Mol. Cell 33, 1-13.
  2. Wei H, Mundade R, Lange KC, et al. (2014) Protein arginine methylation of non-histone proteins and its role in diseases, Cell Cycle 13, 32-41.
  3. Kaniskan HÜ, Konze KD, and Jin J. (2015) Selective Inhibitors of Protein Methyltransferases, J. Med. Chem. 58, 1596-1629.
  4. Yang YZ and Bedford MT (2013) Protein arginine methyltransferases and cancer, Nat. Rev. Cancer 13, 37-50.
  5. Chung J, Karkhanis V, Tae S, et al. (2013) Protein arginine methyltransferase 5 (PRMT5) inhibition induces lymphoma cell death through reactivation of the retinoblastoma tumor suppressor pathway and polycomb repressor complex 2 (PRC2) silencing. J Biol Chem 288, 35534-35547.
  6. Pal S, Baiocchi RA, Byrd JC, et al. (2007) Low levels of miR-92b/96 induce PRMT5 translation and H3R8/H4R3 methylation in mantle cell lymphoma. EMBO J. 26, 3558–3569.
  7. Chan-Penebre E, Kuplast KG, Majer CR, et al. (2015) A selective inhibitor of PRMT with in vivo and in vitro potency in MCL models. Nature Chem Biol. 11, 432-441.
  8. Duncan KW, Rioux N, Boriack-Sjodin PA, et al. (2015) Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666. ACS Med Chem Lett. DOI: 10.1021/acsmedchemlett.5b00380. 
pk properties
co-crystal structures

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PDB 5C9Z
Main features

  1. Peptide structure with SAM analog 
  2. GSK591 with Sinefungin 
  3. GSK591 Key interactions 
synthetic schemes
materials and methods
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