2YER: Synthesis and evaluation of triazolones as checkpoint kinase 1 inhibitors

Checkpoint kinase 1 (Chk1, CHEK1) is a Ser/Thr protein kinase that plays a key role in mediating the cellular response to DNA-damage. Synthesis and evaluation of a previously described class of Chk1 inhibitors, triazoloquinolones/triazolones (TZs) is further described herein. Our investigation of structure-activity relationships led to the identification of potent inhibitors 14c, 14h and 16e. Key challenges included modulation of physicochemical properties and pharmacokinetic (PK) parameters to enable compound testing in a Chk1 specific hollow fiber pharmacodynamic model. In this model, 16e was shown to abrogate topotecan-induced cell cycle arrest in a dose dependent manner. The demonstrated activity of TZs in this model in combination with a chemotherapeutic agent as well as radiotherapy validates this series of Chk1 inhibitors. X-ray crystal structures (PDB code: 2YEX and 2YER) for an initial lead and an optimized analog are also presented.
PDB ID: 2YERDownload
MMDB ID: 97897
PDB Deposition Date: 2011/3/30
Updated in MMDB: 2018/04
Experimental Method:
x-ray diffraction
Resolution: 1.83  Å
Source Organism:
Similar Structures:
Biological Unit for 2YER: monomeric; determined by author and by software (PISA)
Molecular Components in 2YER
Label Count Molecule
Protein (1 molecule)
Serine/threonine-protein Kinase Chk1(Gene symbol: CHEK1)
Molecule annotation
Chemicals (8 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB