PDBsum entry 4anq

Transferase

PDB id: 4anq

Contents

Protein chain

294 a.a.

Ligands

VGH

Waters ×209

PDB id:

4anq

Name:

Transferase

Title:

Structure of g1269a mutant anaplastic lymphoma kinase in complex with crizotinib

Structure:

Alk tyrosine kinase receptor. Chain: a. Fragment: kinase, residues 1093-1411. Synonym: anaplastic lymphoma kinase, cd246. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

1.76Å R-factor: 0.201 R-free: 0.217

Authors:

M.Mctigue,Y.Deng,W.Liu,A.Brooun

Key ref:

Q.Huang et al. (2014). Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib. J Med Chem, 57, 1170-1187. PubMed id: 24432909 DOI: 10.1021/jm401805h

Date:

21-Mar-12 Release date: 27-Mar-13

Protein chain

Q9UM73  (ALK_HUMAN) -  ALK tyrosine kinase receptor from Homo sapiens

Seq: 1620 a.a.

Struc: 294 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor 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/jm401805h

J Med Chem 57:1170-1187 (2014)

PubMed id: 24432909

Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib.

Q.Huang, T.W.Johnson, S.Bailey, A.Brooun, K.D.Bunker, B.J.Burke, M.R.Collins, A.S.Cook, J.J.Cui, K.N.Dack, J.G.Deal, Y.L.Deng, D.Dinh, L.D.Engstrom, M.He, J.Hoffman, R.L.Hoffman, P.S.Johnson, R.S.Kania, H.Lam, J.L.Lam, P.T.Le, Q.Li, L.Lingardo, W.Liu, M.W.Lu, M.McTigue, C.L.Palmer, P.F.Richardson, N.W.Sach, H.Shen, T.Smeal, G.L.Smith, A.E.Stewart, S.Timofeevski, K.Tsaparikos, H.Wang, H.Zhu, J.Zhu, H.Y.Zou, M.P.Edwards.

ABSTRACT

Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).