Discovery of a First-in-Class Inhibitor of the Histone Methyltransferase SETD2 Suitable for Preclinical Studies

  • ACS Med Chem Lett. 2021 Aug 24;12(10):1539-1545. doi: 10.1021/acsmedchemlett.1c00272.
John W Lampe  1 ,  Joshua S Alford  1 ,  P Ann Boriak-Sjodin  1 ,  Dorothy Brach  1 ,  Kat Cosmopoulos  1 ,  Kenneth W Duncan  1 ,  Sean T Eckley  1 ,  Megan A Foley  1 ,  Darren M Harvey  1 ,  Vinny Motwani  1 ,  Michael J Munchhof  1 ,  Alejandra Raimondi  1 ,  Thomas V Riera  1 ,  Cuyue Tang  1 ,  Michael J Thomenius  1 ,  Jennifer Totman  1 ,  Neil A Farrow  1
Affiliations
  • 1. Epizyme Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
PMID: 34671445 DOI: 10.1021/acsmedchemlett.1c00272
Abstract

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.

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