LLY-283

LLY-283 A Chemical Probe For PRMT5.

This probe is available from Sigma and Cayman Chemical.

Its negative control (LLY-284) is available for purchase from Sigma.

The control may be requested by clicking here.

  • overview
  • properties
  • selectivity profile
  • cell based assay data
  • references
  • co-crystal structures
overview
LLY-283LLY-284 (negative control)

 

A collaboration between Eli Lilly and the SGC has resulted in the identification of LLY-283, the first potent and selective SAM-competitive chemical probe for PRMT5. The in vitro activity of LLY-283 includes potent inhibition of PRMT5 enzyme activity with IC50 = 20 nM for methylation of an H4R3 derived peptide substrate, and greater than 100-fold selectivity over other histone methyltransferases and non-epigenetic targets. In cellular assays, LLY-283 inhibits the methylation of SmBB’  with IC50 = 25 nM (MCF7 cells; 3 days) and also affects MDM4 splicing with IC50-relative of 40 nM (A375 cells; 3 days).

A closely related compound, LLY-284, is less potent in the biochemical assay and is an ideal control compound for cellular studies.

properties


LLY-283


LLY-284
(negative control)

Physical and chemical properties for LLY-283
Molecular weight342.1
Molecular formulaC17H18N4O4
IUPAC name2-(5-amino-2,4,9-triaza-bicyclo[4.3.0]nona-1(6),2,4,7-tetraen-9-yl)-5-(hydroxy-phenyl-methyl)-tetrahydro-furan-3,4-diol
MollogP-0.1422
PSA98.65
No. of chiral centres5
No. of rotatable bonds3
No. of hydrogen bond acceptors6
No. of hydrogen bond donors5
Physical and chemical properties for LLY-284 (Negative Control)
Molecular weight342.1
Molecular formulaC17H18N4O4
IUPAC name2-(5-amino-2,4,9-triaza-bicyclo[4.3.0]nona-1(6),2,4,7-tetraen-9-yl)-5-(hydroxy-phenyl-methyl)-tetrahydro-furan-3,4-diol
MollogP-0.1422
PSA98.65
No. of chiral centres5
No. of rotatable bonds3
No. of hydrogen bond acceptors6
No. of hydrogen bond donors5
  • SMILES:
  • LLY-283: c1ccc(cc1)[C@H](C1[C@H]([C@H]([C@H](n2ccc3c(N)ncnc23)O1)O)O)O
  • LLY-284: c1ccc(cc1)C(C1[C@H]([C@H]([C@H](n2ccc3c(N)ncnc23)O1)O)O)O
  • InChI:
  • LLY-284: InChI=1S/C17H18N4O4/c18-15-10-6-7-21(16(10)20-8-19-15)17-13(24)12(23)14(25-17)11(22)9-4-2-1-3-5-9/h1-8,11-14,17,22-24H,(H2,18,19,20)/t11?,12-,13+,14?,17+/m0/s1
  • InChIKey:
  • LLY-283: WWOOWAHTEXIWBO-HLAAWBEZSA-N
  • LLY-284: WWOOWAHTEXIWBO-ZWJXHHABSA-N
selectivity profile
in vitro potency
cell based assay data

Enzyme inhibition assay for LLY-283 and its negative control (LLY-284). The IC50 values of 22 ± 3 nM (Hill Slope of 1) and 1074 ± 53 nM (Hill Slope of 1.2) were determined for LLY-283 (x) and LLY-284 (x), respectively.

 

 

references

Zahid Q. Bonday, Guillermo S. Cortez, Michael J. Grogan, Stephen Antonysamy,  Ken Weichert, Thomas J. Raub, Wayne P. Bocchinfuso,  Fengling Li, Steven Kennedy, Binghui Li, Mary M. Mader, Cheryl H. Arrowsmith, Robert M. Campbell, Peter J. Brown,  Mohammad S. Eram, Magdalena M. Szewczyk, Masoud Vedadi, Dalia Barsyte-Lovejoy. LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with antitumor activity. ACS Med. Chem. Lett. (2018) DOI: 10.1021/acsmedchemlett.8b00014

pk properties
co-crystal structures

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PDB 6CKC
Main features

  1. Tetrameric structure of PRMT5 with LLY-283 
  2. Structure of SAM analog with substrate (PDB: 4GQB) 
  3. Details of LLY-283 binding pocket with H-bonds shown 
  4. Overlay of substrate, LLY-283, and EPZ015666 structures highlighting binding pocket differences 
synthetic schemes
materials and methods
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