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.

• MeSH
• antitumorózní látky chemická syntéza   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• biologické markery MeSH
• buněčný cyklus účinky léků   MeSH
• checkpoint kinasa 1 antagonisté a inhibitory   MeSH
• chemorezistence účinky léků   MeSH
• dealkylace účinky léků   MeSH
• inhibitory proteinkinas chemická syntéza   farmakologie   MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• lidé MeSH
• metylace MeSH
• modely nemocí na zvířatech MeSH
• molekulární struktura MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• pyrazoly farmakologie   MeSH
• pyrimidiny farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH