7TY2
Crystal Structure of SETD2 Bound to an Indole-based Inhibitor
Summary for 7TY2
| Entry DOI | 10.2210/pdb7ty2/pdb |
| Descriptor | Histone-lysine N-methyltransferase SETD2, ZINC ION, S-ADENOSYLMETHIONINE, ... (5 entities in total) |
| Functional Keywords | histone-lysine n-methyltransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 32950.64 |
| Authors | Farrow, N.A. (deposition date: 2022-02-11, release date: 2022-08-31, Last modification date: 2024-04-03) |
| Primary citation | Alford, J.S.,Lampe, J.W.,Brach, D.,Chesworth, R.,Cosmopoulos, K.,Duncan, K.W.,Eckley, S.T.,Kutok, J.L.,Raimondi, A.,Riera, T.V.,Shook, B.,Tang, C.,Totman, J.,Farrow, N.A. Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies. Acs Med.Chem.Lett., 13:1137-1143, 2022 Cited by PubMed Abstract: SETD2, a lysine -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-molecule SETD2 inhibitor tool compound that is suitable for preclinical studies. Herein we describe the conformational-design-driven evolution of the advanced chemistry lead, which resulted in compounds appropriate for clinical evaluation. Further optimization of this chemical 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. PubMed: 35859865DOI: 10.1021/acsmedchemlett.2c00167 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.438 Å) |
Structure validation
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