8P07

Crystal structure of human Casein Kinase II subunit alpha (CK2a1) in complex with 5-((3-(4H-1,2,4-triazol-4-yl)phenyl)amino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

8P07 の概要

• エントリーDOI: 10.2210/pdb8p07/pdb
• 分子名称: Casein kinase II subunit alpha, SULFATE ION, 7-(cyclopropylamino)-5-[[3-(1,2,4-triazol-4-yl)phenyl]amino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, ... (5 entities in total)
• 機能のキーワード: kinase, ck2, typi inhibitor, 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: 82771.73

構造登録者

Kraemer, A.,Ong, H.W.,Yang, X.,Bown, J.W.,Chang, E.,Willson, T.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2023-05-09, 公開日: 2023-05-17, 最終更新日: 2024-08-07)

主引用文献

Ong, H.W.,Yang, X.,Smith, J.L.,Dickmander, R.J.,Brown, J.W.,Havener, T.M.,Taft-Benz, S.,Howell, S.,Sanders, M.K.,Capener, J.L.,Counago, R.M.,Chang, E.,Kramer, A.,Moorman, N.J.,Heise, M.,Axtman, A.D.,Drewry, D.H.,Willson, T.M.
More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5- a ]pyrimidine Host CSNK2 Inhibitors for Combatting beta-Coronavirus Replication.
J.Med.Chem., 67:12261-12313, 2024

PubMed Abstract: The pyrazolo[1,5-]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against β-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5-]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor . Despite excellent in vitro metabolic stability, rapid decline in plasma concentration of in vivo was observed and may be attributed to lung accumulation, although in vivo pharmacological effect was not observed. Further optimization of this novel chemotype may validate CSNK2 as an antiviral target in vivo.

PubMed: 38959455
DOI: 10.1021/acs.jmedchem.4c00962

実験手法

X-RAY DIFFRACTION (2.4 Å)