Discovery of a Novel Class of Triazolones as Checkpoint Kinase Inhibitors-Hit to Lead Exploration.

abstract Checkpoint Kinase-1 (Chk1, CHK1, CHEK1) is a Ser/Thr protein kinase that mediates cellular responses toDNA-damage. A novel class of Chk1 inhibitors, triazoloquinolones/triazolones (TZ’s) was identified byhigh throughput screening. The optimization of these hits to provide a lead series is described. 2010 Elsevier Ltd. All rights reserved. Checkpoint Kinase-1 (Chk1, CHK1, CHEK1) is a Ser/Thr proteinkinase that mediates the cellular response to DNA-damage. UponDNA-damage, Chk1 is activated by ATM and ATR kinases, whichphosphorylate residues Ser-317 and/or Ser-345. Chk1 mediatedsignaling ultimately leads to S-phase or G2/M cell cycle arrest pri-marily driven by Cdk inhibition. Consequently Chk1 inhibitionwouldabrogatethisarrest,andthereforepermitacellwithdamagedDNAtocontinuethroughthecellcycle,ultimatelyresultinginmito-tic catastrophe and/or apoptosis. 1,2 Therefore, Chk1 inhibitors havebeen highly sought after based on their potential to enhance theefficacy of either chemo- or radio-therapeutic treatments.