5QU0

TGF-BETA RECEPTOR TYPE 1 KINASE DOMAIN (T204D) IN COMPLEX WITH 6-[4-(3-CHLORO-4-FLUOROPHENYL)-1-(2-HYDROXYETHYL)-1H-IMIDAZOL-5-YL]IMIDAZO[1,2-B]PYRIDAZINE-3-CARBONITRILE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.178 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGF beta R1 Inhibitor as an Immuno-oncology Agent.

Velaparthi, U.Darne, C.P.Warrier, J.Liu, P.Rahaman, H.Augustine-Rauch, K.Parrish, K.Yang, Z.Swanson, J.Brown, J.Dhar, G.Anandam, A.Holenarsipur, V.K.Palanisamy, K.Wautlet, B.S.Fereshteh, M.P.Lippy, J.Tebben, A.J.Sheriff, S.Ruzanov, M.Yan, C.Gupta, A.Gupta, A.K.Vetrichelvan, M.Mathur, A.Gelman, M.Singh, R.Kinsella, T.Murtaza, A.Fargnoli, J.Vite, G.Borzilleri, R.M.

(2020) ACS Med Chem Lett 11: 172-178

  • DOI: https://doi.org/10.1021/acsmedchemlett.9b00552
  • Primary Citation of Related Structures:  
    5QTZ, 5QU0

  • PubMed Abstract: 

    Novel imidazole-based TGFβR1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochemical characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGFβR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFβ-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGFβR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicology studies and also provided similar efficacy as once daily dosing.


  • Organizational Affiliation

    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
TGF-beta receptor type-1307Homo sapiensMutation(s): 1 
Gene Names: TGFBR1ALK5SKR4
EC: 2.7.11.30
UniProt & NIH Common Fund Data Resources
Find proteins for P36897 (Homo sapiens)
Explore P36897 
Go to UniProtKB:  P36897
PHAROS:  P36897
GTEx:  ENSG00000106799 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP36897
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
QMV (Subject of Investigation/LOI)
Query on QMV

Download Ideal Coordinates CCD File 
B [auth A]6-[4-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1H-imidazol-5-yl]imidazo[1,2-b]pyridazine-3-carbonitrile
C18 H12 Cl F N6 O
VZZBCNXVZFAIQX-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
QMV BindingDB:  5QU0 Ki: min: 0.8, max: 1.4 (nM) from 2 assay(s)
IC50: min: 1.6, max: 350 (nM) from 8 assay(s)
Binding MOAD:  5QU0 IC50: 1.6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.178 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.73α = 90
b = 78.11β = 90
c = 90.47γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
Aimlessdata scaling
AMoREphasing
BUSTERrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2020-02-05 
  • Deposition Author(s): Sheriff, S.

Revision History  (Full details and data files)

  • Version 1.0: 2020-02-05
    Type: Initial release
  • Version 1.1: 2020-03-04
    Changes: Data collection, Database references
  • Version 1.2: 2021-05-12
    Changes: Structure summary
  • Version 1.3: 2021-11-17
    Changes: Database references, Structure summary