PDBsum entry 4ztl

Transferase/transferase inhibitor

PDB id: 4ztl

Contents

Protein chains

283 a.a.

Ligands

4S1 ×4

Waters ×108

PDB id:

4ztl

Name:

Transferase/transferase inhibitor

Title:

Irak4-inhibitor co-structure

Structure:

Interleukin-1 receptor-associated kinase 4. Chain: a, b, c, d. Fragment: unp residues 160-460. Synonym: irak-4,renal carcinoma antigen ny-ren-64. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: irak4. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.39Å R-factor: 0.226 R-free: 0.251

Authors:

T.O.Fischmann

Key ref:

W.M.Seganish et al. (2015). Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors. Acs Med Chem Lett, 6, 942-947. PubMed id: 26288698 DOI: 10.1021/acsmedchemlett.5b00279

Date:

14-May-15 Release date: 02-Sep-15

Protein chains

Q9NWZ3  (IRAK4_HUMAN) -  Interleukin-1 receptor-associated kinase 4 from Homo sapiens

Seq: 460 a.a.

Struc: 283 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

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

reference

DOI no: 10.1021/acsmedchemlett.5b00279

Acs Med Chem Lett 6:942-947 (2015)

PubMed id: 26288698

Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors.

W.M.Seganish, T.O.Fischmann, B.Sherborne, J.Matasi, B.Lavey, W.T.McElroy, D.Tulshian, J.Tata, C.Sondey, C.G.Garlisi, K.Devito, J.Fossetta, D.Lundell, X.Niu.

ABSTRACT

We report the identification and synthesis of a series of aminopyrimidin-4-one IRAK4 inhibitors. Through high throughput screening, an aminopyrimidine hit was identified and modified via structure enabled design to generate a new, potent, and kinase selective pyrimidin-4-one chemotype. This chemotype is exemplified by compound 16, which has potent IRAK4 inhibition activity (IC50 = 27 nM) and excellent kinase selectivity (>100-fold against 99% of 111 tested kinases), and compound 31, which displays potent IRAK4 activity (IC50 = 93 nM) and good rat bioavailability (F = 42%).