作者: Munchhof, Michael J. ; Eckley, Sean T. ; Boriak-Sjodin, P. Ann ; Foley, Megan A. ; Brach, Dorothy ; Riera, Thomas V. ; Totman, Jennifer ; Raimondi, Alejandra ; Motwani, Vinny ; Farrow, Neil A. ; Duncan, Kenneth W. ; Lampe, John W. ; Tang, Cuyue ; Cosmopoulos, Kat ; Alford, Joshua S. ; Harvey, Darren M. ; Thomenius, Michael J.

SET domain-containing protein 2 (SETD2), a histone methyltransferase, has been identified as a target of interest in certain hematological malignancies, including multiple myeloma. This account details the discovery of EPZ-719, a novel and potent SETD2 inhibitor with a high selectivity over other histone methyltransferases. A screening campaign of the Epizyme proprietary histone methyltransferase-biased library identified potential leads based on a 2-amidoindole core. Structure-based drug design (SBDD) and drug metabolism/pharmacokinetics (DMPK) optimization resulted in EPZ-719, an attractive tool compound for the interrogation of SETD2 biology that enables in vivo target validation studies.

ACS Medicinal Chemistry Letters

Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies

作者: Tang, Cuyue ; Eckley, Sean T. ; Totman, Jennifer ; Riera, Thomas V. ; Farrow, Neil A. ; Raimondi, Alejandra ; Alford, Joshua S. ; Kutok, Jeffrey L. ; Brach, Dorothy ; Duncan, Kenneth W. ; Chesworth, Richard ; Lampe, John W. ; Shook, Brian ; Cosmopoulos, Kat

SETD2, a lysine N-methyltransferase, is a histone methyltransferase that plays an important role in various cellular processes and was identified as a target of interest in multiple myeloma that features a t(4,14) translocation.We recently reported the discovery of a novel small-mol. SETD2 inhibitor tool compound that is suitable for preclin. studies.Herein we describe the conformational-design-driven evolution of the advanced chem. lead, which resulted in compounds appropriate for clin. evaluation.Further optimization of this chem. series led to the discovery of EZM0414, which is a potent, selective, and orally bioavailable inhibitor of SETD2 with good pharmacokinetic properties and robust pharmacodynamic activity in a mouse xenograft model.

PLOS Pathogens

The histone methyltransferase SETD2 regulates HIV expression and latency

Article

作者: Bussey-Sutton, Cameron R ; Fox, Joshua A ; Strahl, Brian D ; Gomez-Martinez, Ismael ; Margolis, David M ; Jones, Corbin ; Peterson, Jackson J ; Browne, Edward P ; Ward, Airlie ; Hepperla, Austin ; Emery, Ann ; Turner, Anne-Marie W ; Longoria, Arturo R

Understanding the mechanisms that drive HIV expression and latency is a key goal for achieving an HIV cure. Here we investigate the role of the SETD2 histone methyltransferase, which deposits H3K36 trimethylation (H3K36me3), in HIV infection. We show that prevention of H3K36me3 by a potent and selective inhibitor of SETD2 (EPZ-719) leads to reduced post-integration viral gene expression and accelerated emergence of latently infected cells. CRISPR/Cas9-mediated knockout of SETD2 in primary CD4 T cells confirmed the role of SETD2 in HIV expression. Transcriptomic profiling of EPZ-719-exposed HIV-infected cells identified numerous pathways impacted by EPZ-719. Notably, depletion of H3K36me3 prior to infection did not prevent HIV integration but resulted in a shift of integration sites from highly transcribed genes to quiescent chromatin regions and to polycomb repressed regions. We also observed that SETD2 inhibition did not apparently affect HIV RNA levels, indicating a post-transcriptional mechanism affecting HIV expression. Viral RNA splicing was modestly reduced in the presence of EPZ-719. Intriguingly, EPZ-719 exposure enhanced responsiveness of latent HIV to the HDAC inhibitor vorinostat, suggesting that H3K36me3 can contribute to a repressive chromatin state at the HIV locus. These results identify SETD2 and H3K36me3 as novel regulators of HIV integration, expression and latency.

100 项与 EPZ-719 相关的药物交易

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