PDBsum entry 4b05

Hydrolase

PDB id: 4b05

Contents

Protein chain

371 a.a.

Ligands

ACT ×5

32D

Metals

_NA

Waters ×356

PDB id:

4b05

Name:

Hydrolase

Title:

Preclinical characterization of azd3839, a novel clinical candidate bace1 inhibitor for the treatment of alzheimer disease

Structure:

Beta-secretase 1. Chain: a. Fragment: residues 43-453. Synonym: aspartyl protease 2, asp2, beta-site amyloid precursor protein cleaving enzyme 1, beta-site app cleaving enzyme 1, memapsin- 2, membrane-associated aspartic protease 2. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.80Å R-factor: 0.180 R-free: 0.215

Authors:

F.Jeppsson,S.Eketjall,J.Janson,S.Karlstrom,S.Gustavsson,L.L.Olsson, A.C.Radesater,B.Ploeger,G.Cebers,K.Kolmodin,B.M.Swahn,S.Von Berg, T.Bueters,J.Falting

Key ref:

F.Jeppsson et al. (2012). Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem, 287, 41245-41257. PubMed id: 23048024

Date:

28-Jun-12 Release date: 17-Oct-12

Protein chain

P56817  (BACE1_HUMAN) -  Beta-secretase 1 from Homo sapiens

Seq: 501 a.a.

Struc: 371 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.3.4.23.46 - memapsin 2.

J Biol Chem 287:41245-41257 (2012)

PubMed id: 23048024

Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease.

F.Jeppsson, S.Eketjäll, J.Janson, S.Karlström, S.Gustavsson, L.L.Olsson, A.C.Radesäter, B.Ploeger, G.Cebers, K.Kolmodin, B.M.Swahn, S.von Berg, T.Bueters, J.Fälting.

ABSTRACT

β-Site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processing of the amyloid precursor protein (APP) and formation of amyloid β peptide (Aβ) species. Because cerebral deposition of Aβ species might be critical for the pathogenesis of Alzheimer disease, BACE1 has emerged as a key target for the treatment of this disease. Here, we report the discovery and comprehensive preclinical characterization of AZD3839, a potent and selective inhibitor of human BACE1. AZD3839 was identified using fragment-based screening and structure-based design. In a concentration-dependent manner, AZD3839 inhibited BACE1 activity in a biochemical fluorescence resonance energy transfer (FRET) assay, Aβ and sAPPβ release from modified and wild-type human SH-SY5Y cells and mouse N2A cells as well as from mouse and guinea pig primary cortical neurons. Selectivity against BACE2 and cathepsin D was 14 and >1000-fold, respectively. AZD3839 exhibited dose- and time-dependent lowering of plasma, brain, and cerebrospinal fluid Aβ levels in mouse, guinea pig, and non-human primate. Pharmacokinetic/pharmacodynamic analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects. These results suggest that AZD3839 effectively reduces the levels of Aβ in brain, CSF, and plasma in several preclinical species. It might, therefore, have disease-modifying potential in the treatment of Alzheimer disease and related dementias. Based on the overall pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man.