CCT241533 is a potent and selective inhibitor of CHK2 that potentiates the cytotoxicity of PARP inhibitors.
CCT241533 is a potent and selective inhibitor of CHK2 that potentiates the cytotoxicity of PARP inhibitors.
复制标题
DOI：
10.1158/0008-5472.can-10-1252
复制
发表时间：
2011-01-15
期刊：
影响因子：
11.2
通讯作者：
Garrett MD
中科院分区：
文献类型：
--
作者：
Anderson VE;Walton MI;Eve PD;Boxall KJ;Antoni L;Caldwell JJ;Aherne W;Pearl LH;Oliver AW;Collins I;Garrett MD
CHK 2是一种检查点激酶，参与ATM介导的对双链DNA断裂的反应。其作为药物靶点的潜力尚不清楚，但CHK 2抑制剂可能通过消除导致细胞耐药性的检查点或DNA修复途径之一，提高p53突变背景下遗传毒性癌症治疗的疗效。我们在这里报告的识别和表征的一种新的CHK 2激酶抑制剂，CCT 241533。X射线晶体学证实，CCT 241533结合ATP口袋中的CHK 2。该化合物抑制CHK 2的IC 50为3 nM，并在1 μM时对一组激酶显示出极低的交叉反应性。CCT 241533阻断了人肿瘤细胞系中CHK 2对DNA损伤的反应活性，如通过抑制CHK 2在S516处的自磷酸化、带移迁移率变化和HDMX降解所证明的。在几种细胞系中，CCT 241533未增强选择的遗传毒性剂的细胞毒性。然而，该化合物显著增强了两种结构不同的聚（ADP-核糖）聚合酶（PARP）抑制剂的细胞毒性。单独使用PARP抑制剂时观察到pS516 CHK 2信号的明显诱导，并且该激活被CCT 241533消除，这表明CCT 241533对PARP抑制剂细胞杀伤的增强是由于CHK 2的抑制。因此，CHK 2抑制剂可以与PARP抑制剂组合具有治疗活性。
CHK2 is a checkpoint kinase involved in the ATM-mediated response to double strand DNA breaks. Its potential as a drug target is still unclear but inhibitors of CHK2 may increase the efficacy of genotoxic cancer therapies in a p53 mutant background by eliminating one of the checkpoints or DNA repair pathways contributing to cellular resistance. We report here the identification and characterization of a novel CHK2 kinase inhibitor, CCT241533. X-ray crystallography confirmed that CCT241533 bound to CHK2 in the ATP pocket. This compound inhibits CHK2 with an IC50 of 3 nM and shows minimal cross reactivity against a panel of kinases at 1 μM. CCT241533 blocked CHK2 activity in human tumor cell lines in response to DNA damage, as demonstrated by inhibition of CHK2 autophosphorylation at S516, band-shift mobility changes and HDMX degradation. CCT241533 did not potentiate the cytotoxicity of a selection of genotoxic agents in several cell lines. However, this compound significantly potentiates the cytotoxicity of two structurally distinct Poly (ADP-ribose) polymerase (PARP) inhibitors. Clear induction of the pS516 CHK2 signal was seen with a PARP inhibitor alone and this activation was abolished by CCT241533, implying that the potentiation of PARP inhibitor cell killing by CCT241533 was due to inhibition of CHK2. Consequently CHK2 inhibitors may have therapeutic activity in combination with PARP inhibitors.