LLY-283

LLY-283 : a SAM competitive inhibitor of PRMT5

Structure

SERP Rating

In Cells

(1 ratings)

In Model Organisms

(1 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Probe LLY-283 is in the process of SERP review.

Please continue to check back for new reviews and commentary.

Information

PRMT5

SAM Noncompetitive

up to 1 uM

Probe Availability:

MCULE

In Vitro Validations

Uniprot ID: O14744

Target Class: Epigenetic

Target SubClass: Methyltransferase

Potency: IC50

Potency Value: 22 ± 3 nM

Potency Assay: Radioactivity-based assay assessing methylation of an H4R3 derived peptide substrate

PDB ID for probe-target interaction (3D structure): 6CKC

Target aliases:

Protein arginine N-methyltransferase 5, SKB1, JBP1 ...

DOI Reference: 10.1021/acsmedchemlett.8b00014

Uniprot ID: O14744

Target Class: Epigenetic

Target SubClass: Methyltransferase

Potency: Kd

Potency Value: 6 ± 2 nM

Potency Assay: Surface Plasmon Resonance (SPR

PDB ID for probe-target interaction (3D structure): 6CKC

Target aliases:

Protein arginine N-methyltransferase 5, SKB1, JBP1 ...

DOI Reference: 10.1021/acsmedchemlett.8b00014

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): Selectivity of compounds LLY-283 and LLY-284 at 1 and 10 μM (as indicated on the plot) were assessed against a collection of 32 methyltransferases (f G9a, GLP, SUV39H1, SUV39H2, SETDB1, SETD8, SUV420H1, SUV420H2, SETD7, MLL1 trimeric complex, MLL3 pentameric complex, EZH2 trimeric complex, PRMT1, PRMT3, PRMT4, PRMT5-MEP50 complex, PRMT6, PRMT7, PRMT8, PRMT9, PRDM9, SETD2, SMYD2, and SMYD3).

I have extra information to add

SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

LLY-283 is an excellent probe, for in vitro, in cell, and in vivo studies. It is brain-penetrant and significantly prolongs the survival of mice with orthotopic patient-derived xenografts. It has been reported that it inhibits the increase in PRMT5 expression induced by cisplatin and rescues cisplatin-induced auditory cell apoptosis injury. LLY-283 can also alleviate noise-induced hearing loss and protect against noise-induced damage via activating PI3K/AKT signaling. In the original manuscript, LLY-283 was suggested as a non-competitive inhibitor of PRMT5. Yet, it occupies the SAM-binding pocket of PRMT5-MEP50 complex and actually acts as a competitive inhibitor.

(last updated: 13 Jan 2023 )

Portal Comments

LLY-283 has originally been suggested to be a non-competitive inhibitor or PRMT5, but a subsequent publication showed a competitive binding mode

(last updated: 16 Jan 2023)