9YKS
Crystal structure of the G9a (EHMT2) SET domain in complex with SAM and TNG917
This is a non-PDB format compatible entry.
Summary for 9YKS
| Entry DOI | 10.2210/pdb9yks/pdb |
| Descriptor | Histone-lysine N-methyltransferase EHMT2, ZINC ION, S-ADENOSYLMETHIONINE, ... (7 entities in total) |
| Functional Keywords | methyltransferase, sam, histone, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 135180.51 |
| Authors | Whittington, D.A. (deposition date: 2025-10-07, release date: 2026-05-13, Last modification date: 2026-06-24) |
| Primary citation | Lu, A.Z.,Haines, B.B.,Zhang, W.,Zhang, M.,Whittington, D.A.,Ji, L.,Teng, T.,Dam Ferdinez, M.,Yu, Y.,Zhang, H.,Gu, L.,Tsai, A.W.,Sudsakorn, S.,Mallender, W.D.,Williams, B.D.,Come, J.H.,Throner, S.,Vacca, J.P.,Huang, A.,Min, C.,Maxwell, J.P.,Andersen, J.N.,Chen, Y.P. TNG917 is a Potent and Selective Inhibitor of Histone Lysine Methyltransferases EHMT1/2 that Enhances Anti-Tumor Immunity and Immunotherapy Efficacy. Cancer Res., 2026 Cited by PubMed Abstract: Epigenetic silencing of interferon (IFN) signaling contributes to the resistance of tumors to PD-1/PD-L1 immune checkpoint blockade. In this study, we conducted a fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen to identify tumor-intrinsic regulators of PD-L1 surface expression and identified the histone-lysine methyltransferases EHMT1 and EHMT2 as key suppressors of interferon signaling. TNG917 was developed as a histone substrate-competitive dual inhibitor of EHMT1/2 with low-nanomolar potency in cells and high selectivity over other methyltransferases. In cancer cell lines, TNG917 relieved H3K9-mediated repression, restored interferon-stimulated gene expression, and triggered secretion of T-cell chemoattractant cytokines, including CXCL10. When dosed orally in both syngeneic and humanized mouse models, TNG917 monotherapy led to marked tumor growth inhibition, while combination with anti-PD1 therapy produced complete, durable regressions and established protective immune memory. Early pharmacokinetic and toxicology assessments revealed favorable exposure profiles and a wide safety margin. These findings establish EHMT1/2 inhibition by TNG917 as a strategy to convert immune-cold tumors into T-cell-inflamed lesions and potentiate checkpoint blockade efficacy, supporting its advancement into clinical development in combination with immunotherapy. PubMed: 42268285DOI: 10.1158/0008-5472.CAN-25-4720 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.79 Å) |
Structure validation
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