PDBsum entry 5tts

Transferase/transferase inhibitor

PDB id: 5tts

Contents

Protein chain

274 a.a.

Ligands

7KU

Waters ×184

PDB id:

5tts

Name:

Transferase/transferase inhibitor

Title:

Jak3 with covalent inhibitor 4

Structure:

Tyrosine-protein kinase jak3. Chain: a. Fragment: kinase domain (unp residues 812-1124). Synonym: janus kinase 3,jak-3,leukocyte janus kinase,l-jak. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: jak3. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21.

Resolution:

2.34Å R-factor: 0.205 R-free: 0.263

Authors:

F.F.Vajdos

Key ref:

A.Thorarensen et al. (2017). 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. PubMed id: 28139931 DOI: 10.1021/acs.jmedchem.6b01694

Date:

04-Nov-16 Release date: 22-Feb-17

Protein chain

P52333  (JAK3_HUMAN) -  Tyrosine-protein kinase JAK3 from Homo sapiens

Seq: 1124 a.a.

Struc: 274 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/acs.jmedchem.6b01694

J Med Chem 60:1971-1993 (2017)

PubMed id: 28139931

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.

A.Thorarensen, M.E.Dowty, M.E.Banker, B.Juba, J.Jussif, T.Lin, F.Vincent, R.M.Czerwinski, A.Casimiro-Garcia, R.Unwalla, J.I.Trujillo, S.Liang, P.Balbo, Y.Che, A.M.Gilbert, M.F.Brown, M.Hayward, J.Montgomery, L.Leung, X.Yang, S.Soucy, M.Hegen, J.Coe, J.Langille, F.Vajdos, J.Chrencik, J.B.Telliez.

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.