PF-0477736

PF-0477736 is a potent, selective ATP-competitive inhibitor of Chk1 (Ki = 0.49nM) with 100-fold selectivity over Chk2 (Ki = 47nM). When used in combination with various chemotherapeutics (e.g. gemcitabine and carboplatin), PF-0477736 abrogates DNA damage-induced cell cycle arrest, sensitizes cells to DNA damage, potentiating the antiproliferative effects of these compounds in vitro and in vivo in tumor cell lines and xenografts. PF-0477736 shows <100-fold selectivity for Chk1 over VEGFR2, Fms, Yes, Aurora-A, FGFR3, Flt3 and Ret (Ki = 10, 14, 23, 23, 25 and 39 nM, respectively). Checkpoint kinase 1 (Chk1) belongs to the Ca2+/calmodulin-dependent protein kinase class of enzymes (CAMK). CAMKs are activated by increases in the concentration of intracellular calcium ions (Ca2+) and calmodulin. When activated, the CAMKs transfer phosphates from ATP to defined serine or threonine residues in other proteins, therefore CAMKs are serine/threonine-specific protein kinases. Chk1 regulates S and G2-M phase cell cycle checkpoints in response to DNA damage. Antagonizing the Chk1-mediated cell cycle checkpoints has emerged as an attractive target for anticancer therapy. If Chk1 activity is blocked, DNA-damaged or spindle-disrupted cells would exit cell cycle arrest before full repair and subsequently undergo mitotic catastrophe or cell death. Chk1 inhibitors consequently increase the therapeutic index of DNA-damaging or antimitotic agents as well.