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.

For any inquiries please contact proberequests@thesgc.org.

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Overview


LLY-283	LLY-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 weight	342.1
Molecular formula	C17H18N4O4
IUPAC name	2-(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
PSA	98.65
No. of chiral centres	5
No. of rotatable bonds	3
No. of hydrogen bond acceptors	6
No. of hydrogen bond donors	5

Physical and chemical properties for LLY-284 (Negative Control)
Molecular weight	342.1
Molecular formula	C17H18N4O4
IUPAC name	2-(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
PSA	98.65
No. of chiral centres	5
No. of rotatable bonds	3
No. of hydrogen bond acceptors	6
No. of hydrogen bond donors	5

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-283: 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-/m1/s1

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

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 () and LLY-284 (), respectively.

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

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