4LXD

Bcl_2-Navitoclax Analog (without Thiophenyl) Complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.

Souers, A.J.Leverson, J.D.Boghaert, E.R.Ackler, S.L.Catron, N.D.Chen, J.Dayton, B.D.Ding, H.Enschede, S.H.Fairbrother, W.J.Huang, D.C.Hymowitz, S.G.Jin, S.Khaw, S.L.Kovar, P.J.Lam, L.T.Lee, J.Maecker, H.L.Marsh, K.C.Mason, K.D.Mitten, M.J.Nimmer, P.M.Oleksijew, A.Park, C.H.Park, C.M.Phillips, D.C.Roberts, A.W.Sampath, D.Seymour, J.F.Smith, M.L.Sullivan, G.M.Tahir, S.K.Tse, C.Wendt, M.D.Xiao, Y.Xue, J.C.Zhang, H.Humerickhouse, R.A.Rosenberg, S.H.Elmore, S.W.

(2013) Nat Med 19: 202-208

  • DOI: https://doi.org/10.1038/nm.3048
  • Primary Citation of Related Structures:  
    4LVT, 4LXD, 4MAN

  • PubMed Abstract: 

    Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.


  • Organizational Affiliation

    AbbVie Inc., North Chicago, Illinois, USA. andrew.souers@abbvie.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Apoptosis regulator Bcl-2166Homo sapiensMutation(s): 1 
Gene Names: BCL2
UniProt & NIH Common Fund Data Resources
Find proteins for P10415 (Homo sapiens)
Explore P10415 
Go to UniProtKB:  P10415
PHAROS:  P10415
GTEx:  ENSG00000171791 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP10415
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1XV
Query on 1XV

Download Ideal Coordinates CCD File 
B [auth A]4-(4-{[4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide
C34 H38 Cl N5 O7 S
AJWKZOOIFOHKSK-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1XV PDBBind:  4LXD Ki: 59 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.515α = 90
b = 86.515β = 90
c = 62.425γ = 120
Software Package:
Software NamePurpose
ADSCdata collection
AMoREphasing
BUSTERrefinement
DENZOdata reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2013-08-14 
  • Deposition Author(s): Park, C.H.

Revision History  (Full details and data files)

  • Version 1.0: 2013-08-14
    Type: Initial release
  • Version 1.1: 2017-08-02
    Changes: Refinement description, Source and taxonomy
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations