9EYX の概要
| エントリーDOI | 10.2210/pdb9eyx/pdb |
| 分子名称 | Protein arginine N-methyltransferase 5, N-terminally processed, Methylosome protein WDR77, (3~{S})-2-[(5-azanyl-6-fluoranyl-1~{H}-pyrrolo[3,2-b]pyridin-2-yl)methyl]-6-fluoranyl-1'-[(4-fluorophenyl)methyl]spiro[isoindole-3,3'-pyrrolidine]-1,2'-dione, ... (6 entities in total) |
| 機能のキーワード | methyl transferase, inhibitor, transferase |
| 由来する生物種 | Homo sapiens (human) 詳細 |
| タンパク質・核酸の鎖数 | 2 |
| 化学式量合計 | 110408.77 |
| 構造登録者 | |
| 主引用文献 | Smith, J.M.,Barlaam, B.,Beattie, D.,Bradshaw, L.,Chan, H.M.,Chiarparin, E.,Collingwood, O.,Cooke, S.L.,Cronin, A.,Cumming, I.,Dean, E.,Debreczeni, J.E.,Del Barco Barrantes, I.,Diene, C.,Gianni, D.,Guerot, C.,Guo, X.,Guven, S.,Hayhow, T.G.,Hong, T.,Kemmitt, P.D.,Lamont, G.M.,Lamont, S.,Lynch, J.T.,McWilliams, L.,Moore, S.,Raubo, P.,Robb, G.R.,Robinson, J.,Scott, J.S.,Srinivasan, B.,Steward, O.,Stubbs, C.J.,Syson, K.,Tan, L.,Turner, O.,Underwood, E.,Urosevic, J.,Vazquez-Chantada, M.,Whittaker, A.L.,Wilson, D.M.,Winter-Holt, J.J. Discovery and In Vivo Efficacy of AZ-PRMT5i-1, a Novel PRMT5 Inhibitor with High MTA Cooperativity. J.Med.Chem., 67:13604-13638, 2024 Cited by PubMed Abstract: PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel "MTA-cooperative" compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties. Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available lead compound, ("AZ-PRMT5i-1"), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven efficacy in several MTAP-deficient preclinical cancer models. PubMed: 39080842DOI: 10.1021/acs.jmedchem.4c00097 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (2.2 Å) |
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