8RRQ8RRQ の概要
| エントリーDOI | 10.2210/pdb8rrq/pdb |
| 分子名称 | Tyrosine-protein kinase SYK, N-[(1S,2R)-2-azanylcyclohexyl]-5-[2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl]-2-methyl-pyrazole-3-carboxamide, GLYCEROL, ... (4 entities in total) |
| 機能のキーワード | inhibitor, kinase, transferase |
| 由来する生物種 | Homo sapiens (human) |
| タンパク質・核酸の鎖数 | 1 |
| 化学式量合計 | 33379.28 |
| 構造登録者 | |
| 主引用文献 | Cervi, G.,D'Alessio, R.,Bindi, S.,Buffa, L.,Burocchi, A.,Canevari, G.,Modugno, M.,Motto, I.,Saturno, G.,Orsini, P. Discovery and optimization of 4-pyrazolyl-2-aminopyrimidine derivatives as potent spleen tyrosine kinase (SYK) inhibitors. Eur.J.Med.Chem., 270:116375-116375, 2024 Cited by PubMed Abstract: Spleen tyrosine kinase (Syk) is a key signal transduction mediator of the B cell receptor (BCR) signaling pathway. Abnormal BCR signaling plays a key role in initiation and development of B-cell-derived hematological malignancies, therefore, Syk represents a potential target for inhibiting the BCR signaling resulting in a therapeutic effect in these cancers. Herein, we describe a novel series of SYK inhibitors with 4-(3'-pyrazolyl)-2-amino-pyrimidine scaffold. Extensive study of structure-activity relationships led to the identification of 1 (NMS-0963), a highly potent Syk inhibitor (IC = 3 nM) endowed with high selectivity within a panel of tested kinases and high antiproliferative activity in SYK-dependent BaF3-TEL/SYK cells and in other BCR-dependent hematological tumor cell lines. Additionally, 1 effectively inhibited Syk phosphorylation and downstream signaling mediators of the BCR in treated cells. In in vivo pharmacokinetics studies, 1, displayed good pharmacokinetics properties, with linear exposure with dose and excellent oral bioavailability. These findings suggest that 1 is a promising new Syk inhibitor for treating BCR-dependent hematological cancers. PubMed: 38604095DOI: 10.1016/j.ejmech.2024.116375 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (1.6 Å) |
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