6DA4

JAK3 with Cyanamide CP10

6DA4 の概要

• エントリーDOI: 10.2210/pdb6da4/pdb
• 分子名称: Tyrosine-protein kinase JAK3, (Z)-1-{2,2-difluoro-6-[5-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,3-dihydro-4H-1,4-benzoxazin-4-yl}methanimine (3 entities in total)
• 機能のキーワード: kinase, covalent, transferase-inhibitor complex, transferase/inhibitor
• 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: 36917.01

構造登録者

Vajdos, F.F. (登録日: 2018-05-01, 公開日: 2018-11-28, 最終更新日: 2024-10-23)

主引用文献

Casimiro-Garcia, A.,Trujillo, J.I.,Vajdos, F.,Juba, B.,Banker, M.E.,Aulabaugh, A.,Balbo, P.,Bauman, J.,Chrencik, J.,Coe, J.W.,Czerwinski, R.,Dowty, M.,Knafels, J.D.,Kwon, S.,Leung, L.,Liang, S.,Robinson, R.P.,Telliez, J.B.,Unwalla, R.,Yang, X.,Thorarensen, A.
Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors.
J. Med. Chem., 61:10665-10699, 2018

PubMed Abstract: Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent inhibitors that engage the JAK3 residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated in JAK3 covalent inhibitors. Through crystallography, kinetic, and computational studies, interaction of cyanamide 12 with Cys909 was optimized leading to potent and selective JAK3 inhibitors as exemplified by 32. In relevant cell-based assays and in agreement with previous results from this group, 32 demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses. The contribution from extrahepatic processes to the clearance of cyanamide-based covalent inhibitors was also characterized using metabolic and pharmacokinetic data for 12. This work also gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors.

PubMed: 30423248
DOI: 10.1021/acs.jmedchem.8b01308

実験手法

X-RAY DIFFRACTION (2.9 Å)