Design, synthesis and evaluation of novel thienopyridazine derivatives as Chk1/2 inhibitors.

In order to search for novel checkpoint kinase 1/2 (Chk1) inhibitors, we have designed and synthesized a series of new compounds incorporating thienopyridazine core. Bioevaluation showed that compounds 10j, 10i, 13e and 10o exhibited relatively good inhibitory activity. Notably, compound 10o displayed high selectivity against a panel of kinases and inhibited Chk1/2 signaling pathway stimulated by DNA damage drugs in cellular level. Molecular docking of 10o to the ATP-binding site of Chk1 kinase domain indicated the existence of polar interactions between 10o and the ATP-ribose-binding residues of Chk1. In mouse HT-29 xenografts, a synergistic effect was observed. Co-treatment by CPT-11 and 10o significantly diminished the tumor volume, indicating the great potential of 10o as a candidate of Chk1/2 inhibitor.