5TTS

Jak3 with covalent inhibitor 4

5TTS の概要

• エントリーDOI: 10.2210/pdb5tts/pdb
• 関連するPDBエントリー: 5TTU 5TTV
• 分子名称: Tyrosine-protein kinase JAK3, 1-{(3R)-3-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}propan-1-one (3 entities in total)
• 機能のキーワード: kinase, covalent, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Endomembrane system ; Peripheral membrane protein : P52333
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36816.99

構造登録者

Vajdos, F.F. (登録日: 2016-11-04, 公開日: 2017-02-22, 最終更新日: 2024-10-30)

主引用文献

Thorarensen, A.,Dowty, M.E.,Banker, M.E.,Juba, B.,Jussif, J.,Lin, T.,Vincent, F.,Czerwinski, R.M.,Casimiro-Garcia, A.,Unwalla, R.,Trujillo, J.I.,Liang, S.,Balbo, P.,Che, Y.,Gilbert, A.M.,Brown, M.F.,Hayward, M.,Montgomery, J.,Leung, L.,Yang, X.,Soucy, S.,Hegen, M.,Coe, J.,Langille, J.,Vajdos, F.,Chrencik, J.,Telliez, J.B.
Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans.
J. Med. Chem., 60:1971-1993, 2017

PubMed Abstract: Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in several compounds entering clinical development and two FDA approved NMEs. However, despite significant effort during the past 2 decades, identification of highly selective JAK3 inhibitors has eluded the scientific community. A significant effort within our research organization has resulted in the identification of the first orally active JAK3 specific inhibitor, which achieves JAK isoform specificity through covalent interaction with a unique JAK3 residue Cys-909. The relatively rapid resynthesis rate of the JAK3 enzyme presented a unique challenge in the design of covalent inhibitors with appropriate pharmacodynamics properties coupled with limited unwanted off-target reactivity. This effort resulted in the identification of 11 (PF-06651600), a potent and low clearance compound with demonstrated in vivo efficacy. The favorable efficacy and safety profile of this JAK3-specific inhibitor 11 led to its evaluation in several human clinical studies.

PubMed: 28139931
DOI: 10.1021/acs.jmedchem.6b01694

実験手法

X-RAY DIFFRACTION (2.34 Å)