PDBsum entry 5j7h

Transferase/transferase inhibitor

PDB id: 5j7h

Contents

Protein chain

291 a.a.

Ligands

6GY

Waters ×70

Obsolete entry

PDB id:

5j7h

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of anaplastic lymphoma kinase (alk) bound by brigatinib

Structure:

Alk tyrosine kinase receptor. Chain: a. Fragment: unp residues 1093-1407. Synonym: anaplastic lymphoma kinase. Engineered: yes

Source:

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

Resolution:

1.96Å R-factor: 0.231 R-free: 0.267

Authors:

T.Zhou,L.Parillon,X.Zhu,D.C.Dalgarno

Key ref:

W.S.Huang et al. (2016). Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase. J Med Chem, 59, 4948-4964. PubMed id: 27144831 DOI: 10.1021/acs.jmedchem.6b00306

Date:

06-Apr-16 Release date: 25-May-16

Protein chain

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

Seq: 1620 a.a.

Struc: 291 a.a.

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/acs.jmedchem.6b00306

J Med Chem 59:4948-4964 (2016)

PubMed id: 27144831

Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.

W.S.Huang, S.Liu, D.Zou, M.Thomas, Y.Wang, T.Zhou, J.Romero, A.Kohlmann, F.Li, J.Qi, L.Cai, T.A.Dwight, Y.Xu, R.Xu, R.Dodd, A.Toms, L.Parillon, X.Lu, R.Anjum, S.Zhang, F.Wang, J.Keats, S.D.Wardwell, Y.Ning, Q.Xu, L.E.Moran, Q.K.Mohemmad, H.G.Jang, T.Clackson, N.I.Narasimhan, V.M.Rivera, X.Zhu, D.Dalgarno, W.C.Shakespeare.

ABSTRACT

In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.