Abstract
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.
Highlights
Genomic instability, one of the hallmarks of cancer, is attributed to genetic perturbations caused by both endogenous and exogenous sources
Our results show that MU380 is a comparably selective inhibitor of Checkpoint kinase 1 (CHK1) and significantly more strongly potentiates sensitization to different DNA-damaging drugs across a panel of tumor cell lines
The resulting Suzuki product was fully deprotected and the enantiomers of the corresponding intermediate were separated by highperformance liquid chromatography (HPLC) on chiral stationary phase
Summary
One of the hallmarks of cancer, is attributed to genetic perturbations caused by both endogenous and exogenous sources. Loss of CHK1 in the presence of replication stress created by DNA-damaging drugs has www.aacrjournals.org been reported to be synthetic lethal in tumor cells [6,7,8] This is accompanied by S and G2 arrest caused by combination of CHK1 inhibition with a variety of genotoxic agents [9]. SCH900776 contains the N-methylpyrazole motif, which is one of the most frequent pharmacophores used in medicinal chemistry [15] This moiety has been shown to undergo oxidative demethylation [16] and the resulting metabolite can be the source of undesirable off-target effects (as shown in this study) and/or its formation can cause (at least partly) decreased bioavailability of the parent compound. We have synthesized compound MU380, a fluorinated analogue of SCH900776 possessing highly unusual N-trifluoromethylpyrazole motif, which was envisioned not to undergo metabolic oxidative dealkylation and thereby provide greater robustness to the compound
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