PDBsum entry 4clj

Transferase

PDB id: 4clj

Contents

Protein chain

296 a.a.

Ligands

5P8

Waters ×339

PDB id:

4clj

Name:

Transferase

Title:

Structure of l1196m mutant human anaplastic lymphoma kinase in complex with pf-06463922 ((10r)-7-amino-12-fluoro-2,10,16-trimethyl- 15-oxo- 10,15,16,17-tetrahydro-2h-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile).

Structure:

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

Source:

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

Resolution:

1.66Å R-factor: 0.197 R-free: 0.229

Authors:

M.A.Mctigue,Y.L.Deng,W.Liu,A.Brooun,A.E.Stewart

Key ref:

T.W.Johnson et al. (2014). Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. J Med Chem, 57, 4720-4744. PubMed id: 24819116 DOI: 10.1021/jm500261q

Date:

14-Jan-14 Release date: 28-May-14

Protein chain

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

Seq: 1620 a.a.

Struc: 296 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/jm500261q

J Med Chem 57:4720-4744 (2014)

PubMed id: 24819116

Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.

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

ABSTRACT

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.