4LGE

Crystal structure of clAP1 BIR3 bound to T3261256


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.55 Å
  • R-Value Free: 0.182 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.164 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Design, stereoselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists.

Asano, M.Hashimoto, K.Saito, B.Shiokawa, Z.Sumi, H.Yabuki, M.Yoshimatsu, M.Aoyama, K.Hamada, T.Morishita, N.Dougan, D.R.Mol, C.D.Yoshida, S.Ishikawa, T.

(2013) Bioorg Med Chem 21: 5725-5737

  • DOI: https://doi.org/10.1016/j.bmc.2013.07.020
  • Primary Citation of Related Structures:  
    4LGE, 4LGU

  • PubMed Abstract: 

    We recently reported the discovery of octahydropyrrolo[1,2-a]pyrazine A as a lead compound for an inhibitor of apoptosis proteins (IAP) antagonist. To develop IAP antagonists with favorable PK profiles, we designed novel tri-cyclic compounds, octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazines 1 and 2 based on co-crystal structural analysis of A with cellular IAP-1 (cIAP-1). The additional cyclopropane moiety was used to block the predicted metabolic site of compound A without detriment to the binding affinity for cIAP. Compounds 1 and 2 were stereoselectively synthesized via intermediates 4a and 5b', which were obtained by Simmons-Smith cyclopropanation of ethylester 3a and silyl ether 3b'. Compounds 1 and 2 showed strong growth inhibition in MDA-MB-231 breast cancer cells and improved metabolic stability in comparison to A. Compound 2 exhibited significant in vivo PD effects to increase tumor necrosis factor-alpha mRNA in a dose dependent manner.


  • Organizational Affiliation

    Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan. moriteru.asano@takeda.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Baculoviral IAP repeat-containing protein 2
A, B
115Homo sapiensMutation(s): 0 
Gene Names: API1BIRC2IAP2MIHBRNF48
EC: 6.3.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q13490 (Homo sapiens)
Explore Q13490 
Go to UniProtKB:  Q13490
PHAROS:  Q13490
GTEx:  ENSG00000110330 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13490
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1Y0
Query on 1Y0

Download Ideal Coordinates CCD File 
D [auth A],
F [auth B]
(4S,6aR,7aS)-5-{(2S)-2-cyclohexyl-2-[(N-methyl-L-alanyl)amino]acetyl}-N-[(4R)-3,4-dihydro-2H-chromen-4-yl]octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazine-4-carboxamide
C30 H43 N5 O4
OGTGKCOHYGILPQ-BBAYRLSSSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1Y0 Binding MOAD:  4LGE IC50: 3.5 (nM) from 1 assay(s)
PDBBind:  4LGE IC50: 3.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.55 Å
  • R-Value Free: 0.182 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.164 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 30.52α = 90
b = 72.805β = 90
c = 116.914γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2013-08-28 
  • Deposition Author(s): Dougan, D.R.

Revision History  (Full details and data files)

  • Version 1.0: 2013-08-28
    Type: Initial release
  • Version 1.1: 2024-02-28
    Changes: Data collection, Database references, Derived calculations