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Duncan KW, Rioux N, Boriack-Sjodin PA, et al. Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666. ACS Med Chem Lett. 2015;7(2):162-6doi: 10.1021/acsmedchemlett.5b00380.
Duncan, K. W., Rioux, N., Boriack-Sjodin, P. A., Munchhof, M. J., Reiter, L. A., Majer, C. R., Jin, L., Johnston, L. D., Chan-Penebre, E., Kuplast, K. G., Porter Scott, M., Pollock, R. M., Waters, N. J., Smith, J. J., Moyer, M. P., Copeland, R. A., & Chesworth, R. (2016). Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666. ACS medicinal chemistry letters, 7(2), 162-6. https://doi.org/10.1021/acsmedchemlett.5b00380
Duncan, Kenneth W, et al. "Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666." ACS medicinal chemistry letters vol. 7,2 (2016): 162-6. doi: https://doi.org/10.1021/acsmedchemlett.5b00380
Duncan KW, Rioux N, Boriack-Sjodin PA, Munchhof MJ, Reiter LA, Majer CR, Jin L, Johnston LD, Chan-Penebre E, Kuplast KG, Porter Scott M, Pollock RM, Waters NJ, Smith JJ, Moyer MP, Copeland RA, Chesworth R. Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666. ACS Med Chem Lett. 2015 Dec 02;7(2):162-6. doi: 10.1021/acsmedchemlett.5b00380. eCollection 2016 Feb 11. PMID: 26985292; PMCID: PMC4753547.
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ACS Med Chem Lett. 2015 Dec 02;7(2):162-6. doi: 10.1021/acsmedchemlett.5b00380. eCollection 2016 Feb 11.

Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666.

ACS medicinal chemistry letters

Kenneth W Duncan, Nathalie Rioux, P Ann Boriack-Sjodin, Michael J Munchhof, Lawrence A Reiter, Christina R Majer, Lei Jin, L Danielle Johnston, Elayne Chan-Penebre, Kristy G Kuplast, Margaret Porter Scott, Roy M Pollock, Nigel J Waters, Jesse J Smith, Mikel P Moyer, Robert A Copeland, Richard Chesworth

Affiliations

  1. Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.

PMID: 26985292 PMCID: PMC4753547 DOI: 10.1021/acsmedchemlett.5b00380

Abstract

The recent publication of a potent and selective inhibitor of protein methyltransferase 5 (PRMT5) provides the scientific community with in vivo-active tool compound EPZ015666 (GSK3235025) to probe the underlying pharmacology of this key enzyme. Herein, we report the design and optimization strategies employed on an initial hit compound with poor in vitro clearance to yield in vivo tool compound EPZ015666 and an additional potent in vitro tool molecule EPZ015866 (GSK3203591).

Keywords: Methyltransferase; PRMT5; property based optimization; structure guided design

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