PDBsum entry 4z55

Transferase/transferase inhibitor

PDB id: 4z55

Contents

Protein chain

294 a.a.

Ligands

GOL ×2

4LO

Waters ×197

PDB id:

4z55

Name:

Transferase/transferase inhibitor

Title:

Anaplastic lymphoma kinase catalytic domain complexed with pyrazolopyrimidine derivative of ldk378

Structure:

Alk tyrosine kinase receptor. Chain: a. Fragment: unp residues 1072-1410. Synonym: anaplastic lymphoma kinase. Engineered: yes. Mutation: yes

Source:

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

Resolution:

1.55Å R-factor: 0.186 R-free: 0.208

Authors:

C.C.Lee,G.Spraggon

Key ref:

P.Y.Michellys et al. (2016). Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors. Bioorg Med Chem Lett, 26, 1090-1096. PubMed id: 26750252 DOI: 10.1016/j.bmcl.2015.11.049

Date:

02-Apr-15 Release date: 03-Feb-16

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: 10.1016/j.bmcl.2015.11.049

Bioorg Med Chem Lett 26:1090-1096 (2016)

PubMed id: 26750252

Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors.

P.Y.Michellys, B.Chen, T.Jiang, Y.Jin, W.Lu, T.H.Marsilje, W.Pei, T.Uno, X.Zhu, B.Wu, T.N.Nguyen, B.Bursulaya, C.Lee, N.Li, S.Kim, T.Tuntland, B.Liu, F.Sun, A.Steffy, T.Hood.

ABSTRACT

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g., NPM-ALK in anaplastic large cell lymphoma ALCL or EML4-ALK in non-small cell lung cancer) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.g., neuroblastoma). Here we are reporting the discovery of novel and selective anaplastic lymphoma kinase inhibitors from specific modifications of the 2,4-diaminopyridine core present in TAE684 and LDK378. Synthesis, structure activity relationships (SAR), absorption, distribution, metabolism, and excretion (ADME) profile, and in vivo efficacy in a mouse xenograft model of anaplastic large cell lymphoma are described.