7lzf
Crystal Structure of SETD2 bound to Compound 57
Structural highlights
FunctionSETD2_HUMAN Histone methyltransferase that methylates 'Lys-36' of histone H3. H3 'Lys-36' methylation represents a specific tag for epigenetic transcriptional activation. Probably plays a role in chromatin structure modulation during elongation via its interaction with hyperphosphorylated POLR2A. Binds DNA at promoters. May also act as a transcription activator that binds to promoters. Binds to the promoters of adenovirus 12 E1A gene in case of infection, possibly leading to regulate its expression.[1] Publication Abstract from PubMedSET 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. Discovery of a First-in-Class Inhibitor of the Histone Methyltransferase SETD2 Suitable for Preclinical Studies.,Lampe JW, Alford JS, Boriak-Sjodin PA, Brach D, Cosmopoulos K, Duncan KW, Eckley ST, Foley MA, Harvey DM, Motwani V, Munchhof MJ, Raimondi A, Riera TV, Tang C, Thomenius MJ, Totman J, Farrow NA ACS Med Chem Lett. 2021 Aug 24;12(10):1539-1545. doi:, 10.1021/acsmedchemlett.1c00272. eCollection 2021 Oct 14. PMID:34671445[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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