5T31

Exploiting an Asp-Glu switch in Glycogen Synthase Kinase 3 to design paralog selective inhibitors for use in acute myeloid leukemia


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.85 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.200 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.2 of the entry. See complete history


Literature

Exploiting an Asp-Glu "switch" in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia.

Wagner, F.F.Benajiba, L.Campbell, A.J.Weiwer, M.Sacher, J.R.Gale, J.P.Ross, L.Puissant, A.Alexe, G.Conway, A.Back, M.Pikman, Y.Galinsky, I.DeAngelo, D.J.Stone, R.M.Kaya, T.Shi, X.Robers, M.B.Machleidt, T.Wilkinson, J.Hermine, O.Kung, A.Stein, A.J.Lakshminarasimhan, D.Hemann, M.T.Scolnick, E.Zhang, Y.L.Pan, J.Q.Stegmaier, K.Holson, E.B.

(2018) Sci Transl Med 10

  • DOI: https://doi.org/10.1126/scitranslmed.aam8460
  • Primary Citation of Related Structures:  
    5KPK, 5KPL, 5KPM, 5T31

  • PubMed Abstract: 

    Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class because mutations and overexpression of β-catenin are associated with many cancers. Knockdown of GSK3α or GSK3β individually does not increase β-catenin and offers a conceptual resolution to targeting GSK3: paralog-selective inhibition. However, inadequate chemical tools exist. The design of selective adenosine triphosphate (ATP)-competitive inhibitors poses a drug discovery challenge due to the high homology (95% identity and 100% similarity) in this binding domain. Taking advantage of an Asp 133 →Glu 196 "switch" in their kinase hinge, we present a rational design strategy toward the discovery of paralog-selective GSK3 inhibitors. These GSK3α- and GSK3β-selective inhibitors provide insights into GSK3 targeting in acute myeloid leukemia (AML), where GSK3α was identified as a therapeutic target using genetic approaches. The GSK3α-selective compound BRD0705 inhibits kinase function and does not stabilize β-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells, with no apparent effect on normal hematopoietic cells. Moreover, BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models. These studies demonstrate feasibility of paralog-selective GSK3α inhibition, offering a promising therapeutic approach in AML.


  • Organizational Affiliation

    Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA. fwagner@broadinstitute.org kimberly_stegmaier@dfci.harvard.edu.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glycogen synthase kinase-3 beta
A, B
420Homo sapiensMutation(s): 1 
Gene Names: GSK3B
EC: 2.7.11.26 (PDB Primary Data), 2.7.11.1 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P49841 (Homo sapiens)
Explore P49841 
Go to UniProtKB:  P49841
PHAROS:  P49841
GTEx:  ENSG00000082701 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP49841
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6VL
Query on 6VL

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(4~{S})-4-ethyl-7,7-dimethyl-4-phenyl-2,6,8,9-tetrahydropyrazolo[3,4-b]quinolin-5-one
C20 H23 N3 O
NCKLQXXBRWCYMA-FQEVSTJZSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A, B
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.85 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.200 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 107.957α = 90
b = 84.223β = 94.69
c = 117.218γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-02-21
    Type: Initial release
  • Version 1.1: 2018-03-21
    Changes: Database references
  • Version 2.0: 2019-05-08
    Changes: Atomic model, Data collection, Database references, Derived calculations, Non-polymer description, Structure summary
  • Version 2.1: 2023-10-04
    Changes: Data collection, Database references, Refinement description
  • Version 2.2: 2023-11-15
    Changes: Data collection