PDBsum entry 6tpd

Transferase

PDB id: 6tpd

Contents

Protein chain

289 a.a.

Ligands

QZ8

Waters ×120

PDB id:

6tpd

Name:

Transferase

Title:

Fragment-based discovery of pyrazolopyridones as jak1 inhibitors with excellent subtype selectivity

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

Resolution:

1.99Å R-factor: 0.226 R-free: 0.278

Authors:

B.B.Hansen,T.J.Jepsen,M.Larsen,R.Sindet,T.Vifian,M.N.Burhardt, J.Larsen,J.G.Seitzberg,M.A.Carnerup,A.Jerre,C.Moelck,S.Rai, V.R.Nasipireddy,A.Ritzen

Key ref:

B.B.Hansen et al. (2020). Fragment-Based Discovery of Pyrazolopyridones as JAK1 Inhibitors with Excellent Subtype Selectivity. J Med Chem, 63, 7008-7032. PubMed id: 32462873 DOI: 10.1021/acs.jmedchem.0c00359

Date:

13-Dec-19 Release date: 10-Jun-20

Protein chain

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

Seq: 1132 a.a.

Struc: 289 a.a.*

* PDB and UniProt seqs differ at 4 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/acs.jmedchem.0c00359

J Med Chem 63:7008-7032 (2020)

PubMed id: 32462873

Fragment-Based Discovery of Pyrazolopyridones as JAK1 Inhibitors with Excellent Subtype Selectivity.

B.B.Hansen, T.H.Jepsen, M.Larsen, R.Sindet, T.Vifian, M.N.Burhardt, J.Larsen, J.G.Seitzberg, M.A.Carnerup, A.Jerre, C.Mølck, P.Lovato, S.Rai, V.R.Nasipireddy, A.Ritzén.

ABSTRACT

Herein, we report the discovery of a series of JAK1-selective kinase inhibitors with high potency and excellent JAK family subtype selectivity. A fragment screening hit 1 with a pyrazolopyridone core and a JAK1 bias was selected as the starting point for our fragment-based lead generation efforts. A two-stage strategy was chosen with the dual aims of improving potency and JAK1 selectivity: Optimization of the lipophilic ribose pocket-targeting substituent was followed by the introduction of a variety of P-loop-targeting functional groups. Combining the best moieties from both stages of the optimization afforded compound 40, which showed excellent potency and selectivity. Metabolism studies in vitro and in vivo together with an in vitro safety evaluation suggest that 40 may be a viable lead compound for the development of highly subtype-selective JAK1 inhibitors.