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5TTS

Jak3 with covalent inhibitor 4

Summary for 5TTS
Entry DOI10.2210/pdb5tts/pdb
Related5TTU 5TTV
DescriptorTyrosine-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)
Functional Keywordskinase, covalent, transferase-transferase inhibitor complex, transferase/transferase inhibitor
Biological sourceHomo sapiens (Human)
Cellular locationEndomembrane system ; Peripheral membrane protein : P52333
Total number of polymer chains1
Total formula weight36816.99
Authors
Vajdos, F.F. (deposition date: 2016-11-04, release date: 2017-02-22, Last modification date: 2024-10-30)
Primary citationThorarensen, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.34 Å)
Structure validation

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