3VS0

Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]benzamide

3VS0 の概要

• エントリーDOI: 10.2210/pdb3vs0/pdb
• 関連するPDBエントリー: 3VRY 3VRZ 3VS1 3VS2 3VS3 3VS4 3VS5 3VS6 3VS7
• 分子名称: Tyrosine-protein kinase HCK, CALCIUM ION, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform 1: Lysosome. Isoform 2: Cell membrane; Lipid-anchor. Cytoplasmic vesicle, secretory vesicle: P08631
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 104946.46

構造登録者

Kuratani, M.,Honda, K.,Tomabechi, Y.,Handa, N.,Yokoyama, S. (登録日: 2012-04-21, 公開日: 2013-05-01, 最終更新日: 2023-12-06)

主引用文献

Saito, Y.,Yuki, H.,Kuratani, M.,Hashizume, Y.,Takagi, S.,Honma, T.,Tanaka, A.,Shirouzu, M.,Mikuni, J.,Handa, N.,Ogahara, I.,Sone, A.,Najima, Y.,Tomabechi, Y.,Wakiyama, M.,Uchida, N.,Tomizawa-Murasawa, M.,Kaneko, A.,Tanaka, S.,Suzuki, N.,Kajita, H.,Aoki, Y.,Ohara, O.,Shultz, L.D.,Fukami, T.,Goto, T.,Taniguchi, S.,Yokoyama, S.,Ishikawa, F.
A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo
Sci Transl Med, 5:181ra52-181ra52, 2013

PubMed Abstract: Leukemia stem cells (LSCs) that survive conventional chemotherapy are thought to contribute to disease relapse, leading to poor long-term outcomes for patients with acute myeloid leukemia (AML). We previously identified a Src-family kinase (SFK) member, hematopoietic cell kinase (HCK), as a molecular target that is highly differentially expressed in human primary LSCs compared with human normal hematopoietic stem cells (HSCs). We performed a large-scale chemical library screen that integrated a high-throughput enzyme inhibition assay, in silico binding prediction, and crystal structure determination and found a candidate HCK inhibitor, RK-20449, a pyrrolo-pyrimidine derivative with an enzymatic IC50 (half maximal inhibitory concentration) in the subnanomolar range. A crystal structure revealed that RK-20449 bound the activation pocket of HCK. In vivo administration of RK-20449 to nonobese diabetic (NOD)/severe combined immunodeficient (SCID)/IL2rg(null) mice engrafted with highly aggressive therapy-resistant AML significantly reduced human LSC and non-stem AML burden. By eliminating chemotherapy-resistant LSCs, RK-20449 may help to prevent relapse and lead to improved patient outcomes in AML.

PubMed: 23596204
DOI: 10.1126/scitranslmed.3004387

実験手法

X-RAY DIFFRACTION (2.934 Å)