6B4W

TTK in Complex with Inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen.

Riggs, J.R.Nagy, M.Elsner, J.Erdman, P.Cashion, D.Robinson, D.Harris, R.Huang, D.Tehrani, L.Deyanat-Yazdi, G.Narla, R.K.Peng, X.Tran, T.Barnes, L.Miller, T.Katz, J.Tang, Y.Chen, M.Moghaddam, M.F.Bahmanyar, S.Pagarigan, B.Delker, S.LeBrun, L.Chamberlain, P.P.Calabrese, A.Canan, S.S.Leftheris, K.Zhu, D.Boylan, J.F.

(2017) J Med Chem 60: 8989-9002

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b01223
  • Primary Citation of Related Structures:  
    6B4W

  • PubMed Abstract: 

    Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy.


  • Organizational Affiliation

    Celgene Corporation , 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dual specificity protein kinase TTK303Homo sapiensMutation(s): 0 
Gene Names: TTKMPS1MPS1L1
EC: 2.7.12.1
UniProt & NIH Common Fund Data Resources
Find proteins for P33981 (Homo sapiens)
Explore P33981 
Go to UniProtKB:  P33981
PHAROS:  P33981
GTEx:  ENSG00000112742 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP33981
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CQ7
Query on CQ7

Download Ideal Coordinates CCD File 
B [auth A]4-{[4-(cyclopentyloxy)-5-(2-methyl-1,3-benzoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methoxy-N-methylbenzamide
C28 H28 N6 O4
CWJLAVRXVFHDSJ-UHFFFAOYSA-N
CAC
Query on CAC

Download Ideal Coordinates CCD File 
C [auth A]CACODYLATE ION
C2 H6 As O2
OGGXGZAMXPVRFZ-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
CQ7 BindingDB:  6B4W IC50: min: 5, max: 57 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.194 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.351α = 90
b = 109.581β = 90
c = 114.401γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-10-25
    Type: Initial release
  • Version 2.0: 2017-11-22
    Changes: Database references, Polymer sequence
  • Version 2.1: 2024-03-13
    Changes: Data collection, Database references