5IDN

CDK8-CYCC IN COMPLEX WITH [(S)-2-(4-Chloro-phenyl)-pyrrolidin-1-yl]-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methanone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.26 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.221 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening.

Czodrowski, P.Mallinger, A.Wienke, D.Esdar, C.Poschke, O.Busch, M.Rohdich, F.Eccles, S.A.Ortiz-Ruiz, M.J.Schneider, R.Raynaud, F.I.Clarke, P.A.Musil, D.Schwarz, D.Dale, T.Urbahns, K.Blagg, J.Schiemann, K.

(2016) J Med Chem 59: 9337-9349

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00597
  • Primary Citation of Related Structures:  
    5ICP, 5IDN, 5IDP

  • PubMed Abstract: 

    The mediator complex-associated cyclin dependent kinase CDK8 regulates β-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl-1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies.


  • Organizational Affiliation

    Merck KGaA , Frankfurter Strasse 250, Darmstadt, 64293, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cyclin-dependent kinase 8370Homo sapiensMutation(s): 0 
Gene Names: CDK8
EC: 2.7.11.22 (PDB Primary Data), 2.7.11.23 (PDB Primary Data)
UniProt
Find proteins for P49336-2 (Homo sapiens)
Explore P49336-2 
Go to UniProtKB:  P49336-2
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP49336-2
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Cyclin-C267Homo sapiensMutation(s): 0 
Gene Names: CCNC
UniProt & NIH Common Fund Data Resources
Find proteins for P24863 (Homo sapiens)
Explore P24863 
Go to UniProtKB:  P24863
PHAROS:  P24863
GTEx:  ENSG00000112237 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP24863
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6A7
Query on 6A7

Download Ideal Coordinates CCD File 
C [auth A][(2S)-2-(4-chlorophenyl)pyrrolidin-1-yl](3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone
C18 H17 Cl N4 O
ODRITQGYYWHQGM-INIZCTEOSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
FMT
Query on FMT

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
H [auth B]
I [auth B]
E [auth A],
F [auth A],
G [auth A],
H [auth B],
I [auth B],
J [auth B]
FORMIC ACID
C H2 O2
BDAGIHXWWSANSR-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6A7 BindingDB:  5IDN IC50: min: 2.6, max: 52 (nM) from 6 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.26 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.221 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 70.46α = 90
b = 73.467β = 90
c = 168.02γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling
REFMACrefinement
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-12-21
    Type: Initial release
  • Version 1.1: 2024-01-10
    Changes: Data collection, Database references, Refinement description