4BGH

Crystal Structure of CDK2 in complex with pan-CDK Inhibitor

4BGH の概要

• エントリーDOI: 10.2210/pdb4bgh/pdb
• 分子名称: CYCLIN-DEPENDENT KINASE 2, 4-((5-BROMO-4-(PROP-2-YN-1-YLAMINO)PYRIMIDIN-2-YL)AMINO)BENZENESULFONAMIDE (3 entities in total)
• 機能のキーワード: transferase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: P24941
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34378.75

構造登録者

Luecking, U.,Jautelat, R.,Krueger, M.,Brumby, T.,Lienau, P.,Schaefer, M.,Briem, H.,Schulze, J.,Hillisch, A.,Reichel, A.,Siemeister, G. (登録日: 2013-03-26, 公開日: 2013-09-04, 最終更新日: 2024-05-08)

主引用文献

Lucking, U.,Jautelat, R.,Kruger, M.,Brumby, T.,Lienau, P.,Schafer, M.,Briem, H.,Schulze, J.,Hillisch, A.,Reichel, A.,Wengner, A.M.,Siemeister, G.
The Lab Oddity Prevails: Discovery of Pan-Cdk Inhibitor (R)- S-Cyclopropyl-S-(4-{[4-{[(1R,2R)-2-Hydroxy-1-Methylpropyl]Oxy}-5-(Trifluoromethyl)Pyrimidin-2-Yl]Amino}Phenyl)Sulfoximide (Bay 1000394) for the Treatment of Cancer.
Chemmedchem, 8:1067-, 2013

PubMed Abstract: Lead optimization of a high-throughput screening hit led to the rapid identification of aminopyrimidine ZK 304709, a multitargeted CDK and VEGF-R inhibitor that displayed a promising preclinical profile. Nevertheless, ZK 304709 failed in phase I studies due to dose-limited absorption and high inter-patient variability, which was attributed to limited aqueous solubility and off-target activity against carbonic anhydrases. Further lead optimization efforts to address the off-target activity profile finally resulted in the introduction of a sulfoximine group, which is still a rather unusual approach in medicinal chemistry. However, the sulfoximine series of compounds quickly revealed very interesting properties, culminating in the identification of the nanomolar pan-CDK inhibitor BAY 1000394, which is currently being investigated in phase I clinical trials.

PubMed: 23671017
DOI: 10.1002/CMDC.201300096

実験手法

X-RAY DIFFRACTION (1.95 Å)