PDBsum entry 4c62

Transferase

PDB id: 4c62

Contents

Protein chains

275 a.a.

Ligands

XWW ×2

ACT ×3

Waters ×117

PDB id:

4c62

Name:

Transferase

Title:

Inhibitors of jak2 kinase domain

Structure:

Tyrosine-protein kinase jak2. Chain: a, b. Fragment: kinase domain residues 835-1132. Synonym: janus kinase 2, jak-2. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693. Expression_system_variant: star.

Resolution:

2.75Å R-factor: 0.199 R-free: 0.246

Authors:

J.Read,I.Green,H.Pollard,T.Howard

Key ref:

Q.Su et al. (2014). Discovery of 1-methyl-1H-imidazole derivatives as potent Jak2 inhibitors. J Med Chem, 57, 144-158. PubMed id: 24359159 DOI: 10.1021/jm401546n

Date:

17-Sep-13 Release date: 08-Jan-14

Protein chains

O60674  (JAK2_HUMAN) -  Tyrosine-protein kinase JAK2 from Homo sapiens

Seq: 1132 a.a.

Struc: 275 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

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/jm401546n

J Med Chem 57:144-158 (2014)

PubMed id: 24359159

Discovery of 1-methyl-1H-imidazole derivatives as potent Jak2 inhibitors.

Q.Su, S.Ioannidis, C.Chuaqui, L.Almeida, M.Alimzhanov, G.Bebernitz, K.Bell, M.Block, T.Howard, S.Huang, D.Huszar, J.A.Read, C.Rivard Costa, J.Shi, M.Su, M.Ye, M.Zinda.

ABSTRACT

Structure based design, synthesis, and biological evaluation of a novel series of 1-methyl-1H-imidazole, as potent Jak2 inhibitors to modulate the Jak/STAT pathway, are described. Using the C-ring fragment from our first clinical candidate AZD1480 (24), optimization of the series led to the discovery of compound 19a, a potent, orally bioavailable Jak2 inhibitor. Compound 19a displayed a high level of cellular activity in hematopoietic cell lines harboring the V617F mutation and in murine BaF3 TEL-Jak2 cells. Compound 19a demonstrated significant tumor growth inhibition in a UKE-1 xenograft model within a well-tolerated dose range.