PDBsum entry 4rx5

Transferase

PDB id: 4rx5

Contents

Protein chain

265 a.a.

Ligands

SO4 ×2

GOL ×2

PG0

3YO

Waters ×318

PDB id:

4rx5

Name:

Transferase

Title:

Bruton's tyrosine kinase (btk) with pyridazinone compound 23

Structure:

Tyrosine-protein kinase btk. Chain: a. Fragment: kinase domain (unp residues 393-657). Synonym: agammaglobulinemia tyrosine kinase, atk, b-cell progenitor kinase, bpk, bruton tyrosine kinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: btk, agmx1, atk, bpk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

1.36Å R-factor: 0.161 R-free: 0.179

Authors:

C.Eigenbrot,C.Yu

Key ref:

W.B.Young et al. (2016). Discovery of highly potent and selective Bruton's tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability. Bioorg Med Chem Lett, 26, 575-579. PubMed id: 26675441 DOI: 10.1016/j.bmcl.2015.11.076

Date:

08-Dec-14 Release date: 02-Dec-15

Protein chain

Q06187  (BTK_HUMAN) -  Tyrosine-protein kinase BTK from Homo sapiens

Seq: 659 a.a.

Struc: 265 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: 10.1016/j.bmcl.2015.11.076

Bioorg Med Chem Lett 26:575-579 (2016)

PubMed id: 26675441

Discovery of highly potent and selective Bruton's tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability.

W.B.Young, J.Barbosa, P.Blomgren, M.C.Bremer, J.J.Crawford, D.Dambach, C.Eigenbrot, S.Gallion, A.R.Johnson, J.E.Kropf, S.H.Lee, L.Liu, J.W.Lubach, J.Macaluso, P.Maciejewski, S.A.Mitchell, D.F.Ortwine, J.Di Paolo, K.Reif, H.Scheerens, A.Schmitt, X.Wang, H.Wong, J.M.Xiong, J.Xu, C.Yu, Z.Zhao, K.S.Currie.

ABSTRACT

BTK inhibitor GDC-0834 (1) was found to be rapidly metabolized in human studies, resulting in a suspension of clinical trials. The primary route of metabolism was through cleavage of the acyclic amide bond connecting the terminal tetrahydrobenzothiophene with the central linker aryl ring. SAR studies were focused on reducing metabolic cleavage of this amide, and resulted in the identification of several central aryl linker substituents that conferred improved stability. The most promising substituted aryl linkers were then incorporated into an optimized pyridazinone scaffold, resulting in the identification of lead analog 23, possessing improved potency, metabolic stability and preclinical properties.