7NB4

Structure of Mcl-1 complex with compound 1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.207 

Starting Model: experimental
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This is version 1.1 of the entry. See complete history


Literature

The Effect of Core Replacement on S64315, a Selective MCL-1 Inhibitor, and Its Analogues.

Sipos, S.Balint, B.Szabo, Z.B.Ondi, L.Csekei, M.Szlavik, Z.Proszenyak, A.Murray, J.B.Davidson, J.Chen, I.Dokurno, P.Surgenor, A.E.Pedder, C.Hubbard, R.E.Maragno, A.L.Chanrion, M.Colland, F.Geneste, O.Kotschy, A.

(2021) ACS Omega 6: 22073-22102

  • DOI: https://doi.org/10.1021/acsomega.1c02595
  • Primary Citation of Related Structures:  
    7NB4, 7NB7

  • PubMed Abstract: 

    Following the identification of thieno[2,3- d ]pyrimidine-based selective and potent inhibitors of MCL-1, we explored the effect of core swapping at different levels of advancement. During hit-to-lead optimization, X-ray-guided S-N replacement in the core provided a new vector, whose exploration led to the opening of the so-called deep-S2 pocket of MCL-1. Unfortunately, the occupation of this region led to a plateau in affinity and had to be abandoned. As the project approached selection of a clinical candidate, a series of core swap analogues were also prepared. The affinity and cellular activity of these compounds showed a significant dependence on the core structure. In certain cases, we also observed an increased and accelerated epimerization of the atropoisomers. The most potent core replacement analogues showed considerable in vivo PD response. One compound was progressed into efficacy studies and inhibited tumor growth.


  • 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
Induced myeloid leukemia cell differentiation protein Mcl-1170Homo sapiensMutation(s): 0 
Gene Names: MCL1BCL2L3
UniProt & NIH Common Fund Data Resources
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 GroupQ07820
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
U6Q (Subject of Investigation/LOI)
Query on U6Q

Download Ideal Coordinates CCD File 
B [auth A](2~{R})-2-[[5-(3-chloranyl-2-methyl-phenyl)-6-ethyl-thieno[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid
C24 H22 Cl N3 O2 S
MLKUMODNHNMDBV-GOSISDBHSA-N
PG6
Query on PG6

Download Ideal Coordinates CCD File 
D [auth A]1-(2-METHOXY-ETHOXY)-2-{2-[2-(2-METHOXY-ETHOXY]-ETHOXY}-ETHANE
C12 H26 O6
DMDPGPKXQDIQQG-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
C [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
U6Q BindingDB:  7NB4 Ki: 510 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.207 
  • Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.739α = 90
b = 39.739β = 90
c = 328.268γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2021-10-13
    Type: Initial release
  • Version 1.1: 2024-01-31
    Changes: Data collection, Refinement description