2O1Y

Solution structure of the anti-apoptotic protein Bcl-xL in complex with an acyl-sulfonamide-based ligand


Experimental Data Snapshot

  • Method: SOLUTION NMR
  • Conformers Submitted: 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL.

Bruncko, M.Oost, T.K.Belli, B.A.Ding, H.Joseph, M.K.Kunzer, A.Martineau, D.McClellan, W.J.Mitten, M.Ng, S.C.Nimmer, P.M.Oltersdorf, T.Park, C.M.Petros, A.M.Shoemaker, A.R.Song, X.Wang, X.Wendt, M.D.Zhang, H.Fesik, S.W.Rosenberg, S.H.Elmore, S.W.

(2007) J Med Chem 50: 641-662

  • DOI: https://doi.org/10.1021/jm061152t
  • Primary Citation of Related Structures:  
    2O1Y, 2O21, 2O22, 2O2F, 2O2M, 2O2N

  • PubMed Abstract: 

    Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.


  • Organizational Affiliation

    Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Apoptosis regulator Bcl-X181Homo sapiensMutation(s): 0 
Gene Names: BCL2L1BCL2LBCLX
UniProt & NIH Common Fund Data Resources
Find proteins for Q07817 (Homo sapiens)
Explore Q07817 
Go to UniProtKB:  Q07817
PHAROS:  Q07817
GTEx:  ENSG00000171552 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ07817
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
43B
Query on 43B

Download Ideal Coordinates CCD File 
B [auth A]3-NITRO-N-{4-[2-(2-PHENYLETHYL)-1,3-BENZOTHIAZOL-5-YL]BENZOYL}-4-{[2-(PHENYLSULFANYL)ETHYL]AMINO}BENZENESULFONAMIDE
C36 H30 N4 O5 S3
KYLSTDPZEIQYFX-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: SOLUTION NMR
  • Conformers Submitted: 

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2007-02-27
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2022-03-16
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-12-27
    Changes: Data collection