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Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2017-09-01 00:00:00 , DOI: 10.1158/1535-7163.mct-17-0018
Pounami Samadder 1, 2, 3 , Tereza Suchánková 4 , Ondřej Hylse 5 , Prashant Khirsariya 3, 5 , Fedor Nikulenkov 1, 3 , Stanislav Drápela 4 , Nicol Straková 3, 4 , Petr Vaňhara 3, 6 , Kateřina Vašíčková 3, 6 , Hana Kolářová 1, 2, 3 , Lucia Binó 3, 4 , Miroslava Bittová 3, 5 , Petra Ovesná 4, 7 , Peter Kollár 8 , Radek Fedr 3, 4 , Milan Ešner 6, 8 , Josef Jaroš 3, 6 , Aleš Hampl 3, 6 , Lumír Krejčí 1, 2, 3 , Kamil Paruch 3, 5 , Karel Souček 3, 4, 9
Affiliation  

Checkpoint-mediated dependency of tumor cells can be deployed to selectively kill them without substantial toxicity to normal cells. Specifically, loss of CHK1, a serine threonine kinase involved in the surveillance of the G2–M checkpoint in the presence of replication stress inflicted by DNA-damaging drugs, has been reported to dramatically influence the viability of tumor cells. CHK1′s pivotal role in maintaining genomic stability offers attractive opportunity for increasing the selectivity, effectivity, and reduced toxicity of chemotherapy. Some recently identified CHK1 inhibitors entered clinical trials in combination with DNA antimetabolites. Herein, we report synthesis and profiling of MU380, a nontrivial analogue of clinically profiled compound SCH900776 possessing the highly unusual N-trifluoromethylpyrazole motif, which was envisioned not to undergo metabolic oxidative dealkylation and thereby provide greater robustness to the compound. MU380 is a selective and potent inhibitor of CHK1 which sensitizes a variety of tumor cell lines to hydroxyurea or gemcitabine up to 10 times. MU380 shows extended inhibitory effects in cells, and unlike SCH900776, does not undergo in vivo N-dealkylation to the significantly less selective metabolite. Compared with SCH900776, MU380 in combination with GEM causes higher accumulation of DNA damage in tumor cells and subsequent enhanced cell death, and is more efficacious in the A2780 xenograft mouse model. Overall, MU380 represents a novel state-of-the-art CHK1 inhibitor with high potency, selectivity, and improved metabolic robustness to oxidative N-dealkylation. Mol Cancer Ther; 16(9); 1831–42. ©2017 AACR .

中文翻译:

CHK1激酶的新型有效选择性抑制剂的合成和分析,该抑制剂具有不寻常的抗代谢性N-脱烷基化作用的N-三氟甲基吡唑药理剂

可以部署检查点介导的肿瘤细胞依赖性,以选择性杀死它们,而对正常细胞没有实质性毒性。特别是,据报道,在DNA破坏性药物造成的复制应激的情况下,CHK1(一种参与G2–M检查点监测的丝氨酸苏氨酸激酶)的丢失会极大地影响肿瘤细胞的生存能力。CHK1在维持基因组稳定性中的关键作用为增加化学疗法的选择性,有效性和降低的毒性提供了诱人的机会。最近发现的一些CHK1抑制剂与DNA抗代谢物一起进入临床试验。在此,我们报告了MU380的合成和概况分析,MU380是临床剖析的化合物SCH900776的非平凡类似物,具有非常不寻常的N-三氟甲基吡唑基序,设想其不进行代谢性氧化脱烷基化,从而为该化合物提供更大的坚固性。MU380是CHK1的选择性强效抑制剂,可使多种肿瘤细胞株对羟基脲或吉西他滨的敏感性高达10倍。MU380在细胞中显示出延长的抑制作用,并且与SCH900776不同,MU380不会在体内进行N-脱烷基化作用,以显着降低选择性。与SCH900776相比,MU380与GEM结合会在肿瘤细胞中引起更高的DNA损伤积累,并随后增加细胞死亡,并且在A2780异种移植小鼠模型中更有效。总体而言,MU380代表了一种新型的最新CHK1抑制剂,具有高效力,高选择性和对氧化N-脱烷基反应的改善的代谢稳健性。分子癌疗法;16(9); 1831–42。©2017 AACR。
更新日期:2017-09-05
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