4YBI

Crystal structure of BACE with amino thiazine inhibitor LY2811376


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.84 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.180 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.0 of the entry. See complete history


Literature

Robust central reduction of amyloid-beta in humans with an orally available, non-peptidic beta-secretase inhibitor.

May, P.C.Dean, R.A.Lowe, S.L.Martenyi, F.Sheehan, S.M.Boggs, L.N.Monk, S.A.Mathes, B.M.Mergott, D.J.Watson, B.M.Stout, S.L.Timm, D.E.Smith Labell, E.Gonzales, C.R.Nakano, M.Jhee, S.S.Yen, M.Ereshefsky, L.Lindstrom, T.D.Calligaro, D.O.Cocke, P.J.Greg Hall, D.Friedrich, S.Citron, M.Audia, J.E.

(2011) J Neurosci 31: 16507-16516

  • DOI: https://doi.org/10.1523/JNEUROSCI.3647-11.2011
  • Primary Citation of Related Structures:  
    4YBI

  • PubMed Abstract: 

    According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimer's disease (AD) pathogenesis. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound Aβ-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aβ reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central Aβ reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.


  • Organizational Affiliation

    Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana 46285, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B
442Homo sapiensMutation(s): 0 
Gene Names: BACE1BACEKIAA1149
EC: 3.4.23.46
UniProt & NIH Common Fund Data Resources
Find proteins for P56817 (Homo sapiens)
Explore P56817 
Go to UniProtKB:  P56817
PHAROS:  P56817
GTEx:  ENSG00000186318 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP56817
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
4B2 BindingDB:  4YBI IC50: min: 173, max: 620 (nM) from 7 assay(s)
EC50: 300 (nM) from 1 assay(s)
Binding MOAD:  4YBI IC50: 239 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.84 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.180 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.768α = 90
b = 90.786β = 90
c = 131.753γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2015-04-01 
  • Deposition Author(s): Timm, D.E.

Revision History  (Full details and data files)

  • Version 1.0: 2015-04-01
    Type: Initial release