PDBsum entry 5l3a

Transferase

PDB id: 5l3a

Contents

Protein chain

290 a.a.

Ligands

6DP

Waters ×45

PDB id:

5l3a

Name:

Transferase

Title:

Fragment-based discovery of 6-arylindazole jak inhibitors

Structure:

Tyrosine-protein kinase jak2. Chain: a. Synonym: janus kinase 2,jak-2. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: jak2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21.

Resolution:

1.98Å R-factor: 0.235 R-free: 0.277

Authors:

M.D.Soerensen,K.N.Dack,D.R.Greve,A.Ritzen

Key ref:

A.Ritzén et al. (2016). Fragment-Based Discovery of 6-Arylindazole JAK Inhibitors. Acs Med Chem Lett, 7, 641-646. PubMed id: 27326341 DOI: 10.1021/acsmedchemlett.6b00087

Date:

06-Apr-16 Release date: 27-Apr-16

Protein chain

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

Seq: 1132 a.a.

Struc: 290 a.a.*

* PDB and UniProt seqs differ at 2 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/acsmedchemlett.6b00087

Acs Med Chem Lett 7:641-646 (2016)

PubMed id: 27326341

Fragment-Based Discovery of 6-Arylindazole JAK Inhibitors.

A.Ritzén, M.D.Sørensen, K.N.Dack, D.R.Greve, A.Jerre, M.A.Carnerup, K.A.Rytved, J.Bagger-Bahnsen.

ABSTRACT

Janus kinase (JAK) inhibitors are emerging as novel and efficacious drugs for treating psoriasis and other inflammatory skin disorders, but their full potential is hampered by systemic side effects. To overcome this limitation, we set out to discover soft drug JAK inhibitors for topical use. A fragment screen yielded an indazole hit that was elaborated into a potent JAK inhibitor using structure-based design. Growing the fragment by installing a phenol moiety in the 6-position afforded a greatly improved potency. Fine-tuning the substituents on the phenol and sulfonamide moieties afforded a set of compounds with lead-like properties, but they were found to be phototoxic and unstable in the presence of light.