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Ref Type Journal Article
PMID (28619751)
Authors Samadder P, Suchánková T, Hylse O, Khirsariya P, Nikulenkov F, Drápela S, Straková N, Vaňhara P, Vašíčková K, Kolářová H, Binó L, Bittová M, Ovesná P, Kollár P, Fedr R, Ešner M, Jaroš J, Hampl A, Krejčí L, Paruch K, Souček K
Title Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation.
Journal Molecular cancer therapeutics
Vol 16
Issue 9
Date 2017 Sep
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
MU380 CHK1 Inhibitor 14 MU380 is a selective inhibitor of CHK1, which increases sensitivity of tumor cells to DNA damaging agents, potentially resulting in decreased tumor growth (PMID: 28619751).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown pancreatic carcinoma not applicable Gemcitabine + MU380 Preclinical - Cell line xenograft Actionable In a preclinical study, the addition of MU380 resulted in increased sensitivity to Gemzar (gemcitabine) in a pancreatic carcinoma cell line in culture and in xenograft models (PMID: 28619751). 28619751
Unknown unknown ovarian carcinoma not applicable Gemcitabine + MU380 Preclinical - Cell line xenograft Actionable In a preclinical study, the addition of MU380 resulted in increased sensitivity to Gemzar (gemcitabine) in a ovarian carcinoma cell line, resulting in decreased proliferation in culture and improved survival in xenograft models (PMID: 28619751). 28619751
Unknown unknown renal cell carcinoma not applicable Gemcitabine + MU380 Preclinical - Cell culture Actionable In a preclinical study, the addition of MU380 resulted in increased sensitivity to Gemzar (gemcitabine) in a renal cell carcinoma cell line in culture, leading to decreased proliferation (PMID: 28619751). 28619751
Unknown unknown renal carcinoma not applicable Hydroxyurea + MU380 Preclinical - Cell culture Actionable In a preclinical study, the addition of MU380 resulted in increased sensitivity to Droxia (hydroxyurea) in a renal cell carcinoma cell line in culture, leading to decreased proliferation (PMID: 28619751). 28619751
Unknown unknown colon carcinoma not applicable Hydroxyurea + MU380 Preclinical - Cell culture Actionable In a preclinical study, the addition of MU380 resulted in increased sensitivity to Droxia (hydroxyurea) in colon carcinoma cell lines in culture, leading to decreased proliferation (PMID: 28619751). 28619751