6QXJ

Structure of MBP-Mcl-1 in complex with compound 6a


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.173 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Structure-Guided Discovery of a Selective Mcl-1 Inhibitor with Cellular Activity.

Szlavik, Z.Ondi, L.Csekei, M.Paczal, A.Szabo, Z.B.Radics, G.Murray, J.Davidson, J.Chen, I.Davis, B.Hubbard, R.E.Pedder, C.Dokurno, P.Surgenor, A.Smith, J.Robertson, A.LeToumelin-Braizat, G.Cauquil, N.Zarka, M.Demarles, D.Perron-Sierra, F.Claperon, A.Colland, F.Geneste, O.Kotschy, A.

(2019) J Med Chem 62: 6913-6924

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b00134
  • Primary Citation of Related Structures:  
    6QXJ, 6QYK, 6QYL, 6QYN, 6QYO, 6QYP, 6QZ5, 6QZ6, 6QZ7, 6QZ8, 6QZB

  • PubMed Abstract: 

    Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.


  • Organizational Affiliation

    Servier Research Institute of Medicinal Chemistry , Záhony u. 7. , H-1031 Budapest , Hungary.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Maltose-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1518Escherichia coli O157:H7Homo sapiens
This entity is chimeric
Mutation(s): 6 
Gene Names: malEZ5632ECs5017MCL1BCL2L3
UniProt & NIH Common Fund Data Resources
Find proteins for P0AEX9 (Escherichia coli (strain K12))
Explore P0AEX9 
Go to UniProtKB:  P0AEX9
Find proteins for Q07820 (Homo sapiens)
Explore Q07820 
Go to UniProtKB:  Q07820
PHAROS:  Q07820
GTEx:  ENSG00000143384 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP0AEX9Q07820
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose
B
2N/A
Glycosylation Resources
GlyTouCan:  G07411ON
GlyCosmos:  G07411ON
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
JKQ (Subject of Investigation/LOI)
Query on JKQ

Download Ideal Coordinates CCD File 
C [auth A](2~{R})-2-[[6-ethyl-5-(1~{H}-indol-5-yl)thieno[2,3-d]pyrimidin-4-yl]amino]propanoic acid
C19 H18 N4 O2 S
QOISOOHIVJLDFS-SNVBAGLBSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
D [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
JKQ BindingDB:  6QXJ Ki: 2.20e+4 (nM) from 1 assay(s)
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.173 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 99.21α = 90
b = 135.95β = 90
c = 37.8γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
REFMACrefinement
PDB_EXTRACTdata extraction
XSCALEdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2019-08-07
    Type: Initial release
  • Version 1.1: 2019-08-21
    Changes: Data collection, Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Non-polymer description, Refinement description, Structure summary
  • Version 2.1: 2024-01-24
    Changes: Data collection, Database references, Refinement description, Structure summary