› 5f4n

X-ray diffraction
1.91Å resolution

Multi-parameter lead optimization to give an oral CHK1 inhibitor clinical candidate: (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

Released:
DOI: 10.2210/pdb5f4n/pdb
PDB entry 5f4n coloured by chain, front view.
PDB entry 5f4n coloured by chain, side view.
PDB entry 5f4n coloured by chain, top view.
Source organism: Homo sapiens
Primary publication:
Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737).
Osborne JD, Matthews TP, McHardy T, Proisy N, Cheung KM, Lainchbury M, Brown N, Walton MI, Eve PD, Boxall KJ, Hayes A, Henley AT, Valenti MR, De Haven Brandon AK, Box G, Jamin Y, Robinson SP, Westwood IM, van Montfort RL, Leonard PM, Lamers MB, Reader JC, Aherne GW, Raynaud FI, Eccles SA, Garrett MD, Collins I
J Med Chem 59 5221-37 (2016)
PMID: 27167172

Function and Biology Details

Reaction catalysed: 
ATP + a protein = ADP + a phosphoprotein
Biochemical function:
Biological process:
Cellular component:
  • not assigned
Sequence domains:

Structure analysis Details

Assembly composition:
monomeric (preferred)
Assembly name:
PDBe Complex ID:
PDB-CPX-127093 (preferred)
Entry contents:
1 distinct polypeptide molecule
Macromolecule:
Serine/threonine-protein kinase Chk1 Chain: A
Molecule details ›
Chain: A
Length: 273 amino acids
Theoretical weight: 31.46 KDa
Source organism: Homo sapiens
Expression system: Not provided
UniProt:
  • Canonical: O14757 (Residues: 1-273; Coverage: 57%)
Gene names: CHEK1, CHK1
Sequence domains: Protein kinase domain
Structure domains:

Ligands and Environments

3 bound ligands:
Ligand 5UY 2 x 5UY
Ligand EDO 4 x EDO
Ligand GOL 2 x GOL
No modified residues

Experiments and Validation Details

Entry percentile scores
X-ray source: RIGAKU MICROMAX-007 HF
Spacegroup: P21
Unit cell:
a: 44.97Å b: 65.87Å c: 57.9Å
α: 90° β: 94.69° γ: 90°
R-values:
R R work R free
0.151 0.149 0.188
Expression system: Not provided

Quick links

Citations

5 citation in other articles

CHK1 Inhibition Is Synthetically Lethal with Loss of B-Family DNA Polymerase Function in Human Lung and Colorectal Cancer Cells.
Rogers et al. (2020)
4 more