6T3C

Crystal structure of PI3Kgamma in complex with DNA-PK inhibitor AZD7648

6T3C の概要

• エントリーDOI: 10.2210/pdb6t3c/pdb
• 関連するPDBエントリー: 6T3B
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(oxan-4-yl)purin-8-one (2 entities in total)
• 機能のキーワード: kinase fold, type i kinase inhibitor, structure based drug design, 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: 111107.51

構造登録者

Schimpl, M.,Goldberg, F.W.,Finlay, M.R.V.,Ting, A.K.T.,Beattie, D.,Lamont, G.M.,Fallan, C.,Wrigley, G.L.,Howard, M.R.,Williamson, B.,Davies, B.R.,Cadogan, E.B.,Ramos-Montoya, A.,Dean, E. (登録日: 2019-10-10, 公開日: 2020-01-01, 最終更新日: 2024-01-24)

主引用文献

Goldberg, F.W.,Finlay, M.R.V.,Ting, A.K.T.,Beattie, D.,Lamont, G.M.,Fallan, C.,Wrigley, G.L.,Schimpl, M.,Howard, M.R.,Williamson, B.,Vazquez-Chantada, M.,Barratt, D.G.,Davies, B.R.,Cadogan, E.B.,Ramos-Montoya, A.,Dean, E.
The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor.
J.Med.Chem., 63:3461-3471, 2020

PubMed Abstract: DNA-PK is a key component within the DNA damage response, as it is responsible for recognizing and repairing double-strand DNA breaks (DSBs) via non-homologous end joining. Historically it has been challenging to identify inhibitors of the DNA-PK catalytic subunit (DNA-PKcs) with good selectivity versus the structurally related PI3 (lipid) and PI3K-related protein kinases. We screened our corporate collection for DNA-PKcs inhibitors with good PI3 kinase selectivity, identifying compound . Optimization focused on further improving selectivity while improving physical and pharmacokinetic properties, notably co-optimization of permeability and metabolic stability, to identify compound (AZD7648). Compound had no significant off-target activity in the protein kinome and only weak activity versus PI3Kα/γ lipid kinases. Monotherapy activity in murine xenograft models was observed, and regressions were observed when combined with inducers of DSBs (doxorubicin or irradiation) or PARP inhibition (olaparib). These data support progression into clinical studies (NCT03907969).

PubMed: 31851518
DOI: 10.1021/acs.jmedchem.9b01684

実験手法

X-RAY DIFFRACTION (2.62 Å)