3UW4

Crystal structure of cIAP1 BIR3 bound to GDC0152


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.181 

wwPDB Validation   3D Report Full Report


This is version 1.6 of the entry. See complete history


Literature

Discovery of a Potent Small-Molecule Antagonist of Inhibitor of Apoptosis (IAP) Proteins and Clinical Candidate for the Treatment of Cancer (GDC-0152).

Flygare, J.A.Beresini, M.Budha, N.Chan, H.Chan, I.T.Cheeti, S.Cohen, F.Deshayes, K.Doerner, K.Eckhardt, S.G.Elliott, L.O.Feng, B.Franklin, M.C.Reisner, S.F.Gazzard, L.Halladay, J.Hymowitz, S.G.La, H.Lorusso, P.Maurer, B.Murray, L.Plise, E.Quan, C.Stephan, J.P.Young, S.G.Tom, J.Tsui, V.Um, J.Varfolomeev, E.Vucic, D.Wagner, A.J.Wallweber, H.J.Wang, L.Ware, J.Wen, Z.Wong, H.Wong, J.M.Wong, M.Wong, S.Yu, R.Zobel, K.Fairbrother, W.J.

(2012) J Med Chem 55: 4101-4113

  • DOI: https://doi.org/10.1021/jm300060k
  • Primary Citation of Related Structures:  
    3UW4, 3UW5

  • PubMed Abstract: 

    A series of compounds were designed and synthesized as antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus, AVPI, of mature Smac. Compound 1 (GDC-0152) has the best profile of these compounds; it binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with K(i) values of 28, 14, 17, and 43 nM, respectively. These compounds promote degradation of cIAP1, induce activation of caspase-3/7, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Compound 1 inhibits tumor growth when dosed orally in the MDA-MB-231 breast cancer xenograft model. Compound 1 was advanced to human clinical trials, and it exhibited linear pharmacokinetics over the dose range (0.049 to 1.48 mg/kg) tested. Mean plasma clearance in humans was 9 ± 3 mL/min/kg, and the volume of distribution was 0.6 ± 0.2 L/kg.


  • Organizational Affiliation

    Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. jflygare@gene.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Baculoviral IAP repeat-containing protein 2, Baculoviral IAP repeat-containing protein 492Homo sapiensMutation(s): 3 
Gene Names: API1BIRC2cIAP1IAP2MIHBRNF48API3BIRC4IAP3XIAP
UniProt & NIH Common Fund Data Resources
Find proteins for P98170 (Homo sapiens)
Explore P98170 
Go to UniProtKB:  P98170
PHAROS:  P98170
GTEx:  ENSG00000101966 
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 GroupsP98170Q13490
Sequence Annotations
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
GDC0152B [auth Z]4N/AMutation(s): 0 
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
MAA
Query on MAA
B [auth Z]L-PEPTIDE LINKINGC4 H9 N O2ALA
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.181 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 35.691α = 90
b = 37.38β = 90
c = 57.598γ = 90
Software Package:
Software NamePurpose
BOSdata collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-22
    Type: Initial release
  • Version 1.1: 2012-03-28
    Changes: Database references
  • Version 1.2: 2012-05-23
    Changes: Database references
  • Version 1.3: 2012-12-12
    Changes: Other
  • Version 1.4: 2017-08-02
    Changes: Refinement description, Source and taxonomy
  • Version 1.5: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.6: 2023-12-06
    Changes: Data collection