5ZXB

Crystal structure of ACK1 with compound 10d

5ZXB の概要

• エントリーDOI: 10.2210/pdb5zxb/pdb
• 分子名称: Activated CDC42 kinase 1, N-{3-[7-{[6-(4-acetylpiperazin-1-yl)pyridin-3-yl]amino}-1-methyl-2-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl]-4-methylphenyl}-3-(trifluoromethyl)benzamide (3 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: 2
• 化学式量合計: 64165.94

構造登録者

Hong, E.M.,Kim, H.L.,Sim, T.B. (登録日: 2018-05-18, 公開日: 2018-09-26, 最終更新日: 2024-03-27)

主引用文献

Cho, H.,Shin, I.,Ju, E.,Choi, S.,Hur, W.,Kim, H.,Hong, E.,Kim, N.D.,Choi, H.G.,Gray, N.S.,Sim, T.
First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia.
J. Med. Chem., 61:8353-8373, 2018

PubMed Abstract: GNF-7, a multitargeted kinase inhibitor, served as a dual kinase inhibitor of ACK1 and GCK, which provided a novel therapeutic strategy for overriding AML expressing NRAS mutation. This SAR study with GNF-7 derivatives, designed to target NRAS mutant-driven AML, led to identification of the extremely potent inhibitors, 10d, 10g, and 11i, which possess single-digit nanomolar inhibitory activity against both ACK1 and GCK. These substances strongly suppress proliferation of mutant NRAS expressing AML cells via apoptosis and AKT/mTOR signaling blockade. Compound 11i is superior to GNF-7 in terms of kinase inhibitory activity, cellular activity, and differential cytotoxicity. Moreover, 10k possessing a favorable mouse pharmacokinetic profile prolonged life-span of Ba/F3-NRAS-G12D injected mice and significantly delayed tumor growth of OCI-AML3 xenograft model without causing the prominent level of toxicity found with GNF-7. Taken together, this study provides insight into the design of novel ACK1 and GCK dual inhibitors for overriding NRAS mutant-driven AML.

PubMed: 30153003
DOI: 10.1021/acs.jmedchem.8b00882

実験手法

X-RAY DIFFRACTION (2.198 Å)