5HBE

CDK8-CYCC IN COMPLEX WITH 8-[3-Chloro-5-(1-methyl-2,2-dioxo-2, 3-dihydro-1H-2l6-benzo[c]isothiazol-5-yl)-pyridin- 4-yl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.38 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.230 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.

Mallinger, A.Schiemann, K.Rink, C.Stieber, F.Calderini, M.Crumpler, S.Stubbs, M.Adeniji-Popoola, O.Poeschke, O.Busch, M.Czodrowski, P.Musil, D.Schwarz, D.Ortiz-Ruiz, M.J.Schneider, R.Thai, C.Valenti, M.de Haven Brandon, A.Burke, R.Workman, P.Dale, T.Wienke, D.Clarke, P.A.Esdar, C.Raynaud, F.I.Eccles, S.A.Rohdich, F.Blagg, J.

(2016) J Med Chem 59: 1078-1101

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01685
  • Primary Citation of Related Structures:  
    5FGK, 5HBE, 5HBH, 5HBJ

  • PubMed Abstract: 

    The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.


  • Organizational Affiliation

    Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cyclin-dependent kinase 8364Homo sapiensMutation(s): 0 
Gene Names: CDK8
EC: 2.7.11.22 (PDB Primary Data), 2.7.11.23 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P49336 (Homo sapiens)
Explore P49336 
Go to UniProtKB:  P49336
PHAROS:  P49336
GTEx:  ENSG00000132964 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP49336
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Cyclin-C266Homo 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 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5Y6
Query on 5Y6

Download Ideal Coordinates CCD File 
C [auth A]8-[3-chloranyl-5-[1-methyl-2,2-bis(oxidanylidene)-3~{H}-2,1-benzothiazol-5-yl]pyridin-4-yl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one
C20 H21 Cl N4 O4 S
ZNMSRFYDOSAZLZ-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
D [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
EDO
Query on EDO

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

Download Ideal Coordinates CCD File 
F [auth A],
G [auth B],
H [auth B],
I [auth B]
FORMIC ACID
C H2 O2
BDAGIHXWWSANSR-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5Y6 Binding MOAD:  5HBE IC50: 2.3 (nM) from 1 assay(s)
BindingDB:  5HBE IC50: 2.3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.38 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.230 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.007α = 90
b = 71.115β = 90
c = 173.152γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-02-03
    Type: Initial release
  • Version 1.1: 2016-02-24
    Changes: Database references