EPZ015666

Description

EPZ015666 (GSK3235025) is an orally available inhibitor of protein arginine methyltransferase-5 (PRMT5), which is involved in diverse cellular processes, including tumorigenesis, and its overexpression is observed in cell lines and primary patient samples derived from lymphomas, particularly mantle cell lymphoma (MCL).EPZ015666 showed dose-dependent antitumor activity in multiplein vitroandin vivomantle cell lymphoma (MCL) models with treatment of MCL cell lines leading to inhibition of SmD3 methylation and cell death. Therefore, it is a potential drug candidate for future cancer therapy. 

References

Chan-Penebre, E, et al. "A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models." Nature Chemical Biology 11.6(2015):432.
Duncan, K. W., et al. "Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666." Acs Medicinal Chemistry Letters 7.2(2016):162-166.
http://www.sigmaaldrich.com/catalog/product/sigma/sml1421?lang=en&region=US

Description

EPZ015666 (1616391-65-1) is a selective and potent (IC50= 22nM) inhibitor of arginine methyltransferase 5 (PRMT5).1,2PRMT5 inhibition with EPZ015666 potently suppressedin vivoglioblastoma tumors3and significantly inhibited the growth of multiple myeloma cell lines4.

Uses

Protein arginine methyltransferases (PRMTs) target nuclear and cytoplasmic substrates and can alter protein actions and gene expression. PRMT5, which can methylate histones H2A, H3, and H4, ribonucleoproteins, and other proteins, is upregulated in several human cancers, including lymphomas. Moreover, suppression of PRMT5 expression induces lymphoma cell death. EPZ015666 is a potent, orally bioavailable inhibitor of PRMT5 (Ki = 5 nM). It displays more than 20,000-fold selectivity for PRMT5 over other PMTs. EPZ015666 acts by blocking the association of PRMT5 with methylosome protein 50, which is necessary for the formation of an active methyltransferase complex. EPZ015666 (100 mg/kg twice daily) blocks the growth of mantle cell lymphoma Z-138 xenografts, without significant body weight loss, in mice.[Cayman Chemical]

Uses

EPZ015666 is a potent, orally bioavailable inhibitor of Protein arginine methyltransferase 5 (PRMT5). It acts by blocking the association of PRMT5 with methylosome protein 50.

Biochem/physiol Actions

EPZ015666 (GSK3235025) is a protein arginine methyltransferase PRMT5 inhibitor with an IC50 value of of 22 nM in biochemical assays and no inhibition up to the maximum tested concentration of 50 μM against a panel of 20 other protein methyltransferases. Inhibition was uncompetitive with respect to SAM. EPZ015666 showed dose-dependent antitumor activity in multiple in vitro and in vivo mantle cell lymphoma (MCL) models with treatment of MCL cell lines leading to inhibition of SmD3 methylation and cell death.

in vivo

IC 50

PRMT5

storage

Store at -20°C

References

[1] ELAYNE CHAN-PENEBRE. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models[J]. Nature chemical biology, 2015, 11 6: 432-437. DOI:10.1038/nchembio.1810
[2] KENNETH W. DUNCAN*. Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666[J]. ACS Medicinal Chemistry Letters, 2015, 7 2: 162-166. DOI:10.1021/acsmedchemlett.5b00380
[3] CHRISTIAN J BRAUN. Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma.[J]. Cancer Cell, 2017, 32 4: 411-426.e11. DOI:10.1016/j.ccell.2017.08.018
[4] A GULLÀ. Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma[J]. Leukemia, 2017, 32 4: 996-1002. DOI:10.1038/leu.2017.334