7O2V

AURORA KINASE A IN COMPLEX WITH THE AUR-A/PDK1 INHIBITOR VI8

7O2V の概要

• エントリーDOI: 10.2210/pdb7o2v/pdb
• 分子名称: Aurora kinase A, 1-[[3,4-bis(fluoranyl)phenyl]methyl]-~{N}-[(1~{R})-2-[[(3~{E})-3-(1~{H}-imidazol-5-ylmethylidene)-2-oxidanylidene-1~{H}-indol-5-yl]amino]-2-oxidanylidene-1-phenyl-ethyl]-6-methyl-2-oxidanylidene-pyridine-3-carboxamide (3 entities in total)
• 機能のキーワード: serine/threonine, kinase, aurora, inhibitor, crystal, complex, cancer, tumor, dual, atp-binding, structure-based, drug design, sbdd, 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: 35495.38

構造登録者

Garau, G. (登録日: 2021-03-31, 公開日: 2021-10-20, 最終更新日: 2024-01-31)

主引用文献

Sestito, S.,Bacci, A.,Chiarugi, S.,Runfola, M.,Gado, F.,Margheritis, E.,Gul, S.,Riveiro, M.E.,Vazquez, R.,Huguet, S.,Manera, C.,Rezai, K.,Garau, G.,Rapposelli, S.
Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile.
Eur.J.Med.Chem., 226:113895-113895, 2021

PubMed Abstract: We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma.

PubMed: 34624821
DOI: 10.1016/j.ejmech.2021.113895

実験手法

X-RAY DIFFRACTION (3.1 Å)