6DA4
JAK3 with Cyanamide CP10
Summary for 6DA4
| Entry DOI | 10.2210/pdb6da4/pdb |
| Descriptor | 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) |
| Functional Keywords | kinase, covalent, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 36917.01 |
| Authors | Vajdos, F.F. (deposition date: 2018-05-01, release date: 2018-11-28, Last modification date: 2024-10-23) |
| Primary citation | 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 Cited by 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: 30423248DOI: 10.1021/acs.jmedchem.8b01308 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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