Synthesis and Profiling of a Novel Potent Selective Inhibitor
of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole
Pharmacophore Resistant to Metabolic N-dealkylation

J 2017

Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation

SAMADDER, Pounami, Tereza SUCHÁNKOVÁ, Ondřej HYLSE, PrashantKumar KHIRSARIYA, Fedor NIKULENKOV et. al.

Basic information

Original name

Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation

Authors

SAMADDER, Pounami (356 India, belonging to the institution), Tereza SUCHÁNKOVÁ (203 Czech Republic), Ondřej HYLSE (203 Czech Republic, belonging to the institution), PrashantKumar KHIRSARIYA (356 India, belonging to the institution), Fedor NIKULENKOV (643 Russian Federation, belonging to the institution), Stanislav DRÁPELA (203 Czech Republic), Nicol STRAKOVÁ (203 Czech Republic), Petr VAŇHARA (203 Czech Republic, belonging to the institution), Kateřina VAŠÍČKOVÁ (203 Czech Republic, belonging to the institution), Hana KOLÁŘOVÁ (203 Czech Republic, belonging to the institution), Lucia BINÓ (703 Slovakia), Miroslava BITTOVÁ (203 Czech Republic, belonging to the institution), Petra OVESNÁ (203 Czech Republic, belonging to the institution), Peter KOLLÁR (203 Czech Republic), Radek FEDR (203 Czech Republic), Milan EŠNER (203 Czech Republic, belonging to the institution), Josef JAROŠ (203 Czech Republic, belonging to the institution), Aleš HAMPL (203 Czech Republic, belonging to the institution), Lumír KREJČÍ (203 Czech Republic, belonging to the institution), Kamil PARUCH (203 Czech Republic, belonging to the institution) and Karel SOUČEK (203 Czech Republic, belonging to the institution)

Edition

Molecular Cancer Therapeutics, Philadelphia, American Association for Cancer Research, 2017, 1535-7163

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.365

RIV identification code

RIV/00216224:14110/17:00095657

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1158/1535-7163.MCT-17-0018

UT WoS

000409550300009

Keywords in English

Synthesis and Profiling of a Novel Potent Selective Inhibitor

Abstract

V originále

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. CHK10s 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.

Links

EE2.3.20.0185, research and development project

Name: Centrum analýz a modelování tkání a orgánů

LM2015063, research and development project

Name: Národní infrastruktura chemické biologie (Acronym: CZ-OPENSCREEN)

Investor: Ministry of Education, Youth and Sports of the CR

NV15-33999A, research and development project

Name: Vývoj nových nízkomolekulárních protinádorových léčiv na principu syntetické letality

Citovat

SAMADDER, Pounami, Tereza SUCHÁNKOVÁ, Ondřej HYLSE, PrashantKumar KHIRSARIYA, Fedor NIKULENKOV, Stanislav DRÁPELA, Nicol STRAKOVÁ, Petr VAŇHARA, Kateřina VAŠÍČKOVÁ, Hana KOLÁŘOVÁ, Lucia BINÓ, Miroslava BITTOVÁ, Petra OVESNÁ, Peter KOLLÁR, Radek FEDR, Milan EŠNER, Josef JAROŠ, Aleš HAMPL, Lumír KREJČÍ, Kamil PARUCH and Karel SOUČEK. 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. Philadelphia: American Association for Cancer Research, 2017, vol. 16, No 9, p. 1831-1842. ISSN 1535-7163. Available from: https://dx.doi.org/10.1158/1535-7163.MCT-17-0018.

@article{1388764,
   author = {Samadder, Pounami and Suchánková, Tereza and Hylse, Ondřej and Khirsariya, PrashantKumar and Nikulenkov, Fedor and Drápela, Stanislav and Straková, Nicol and Vaňhara, Petr and Vašíčková, Kateřina and Kolářová, Hana and Binó, Lucia and Bittová, Miroslava and Ovesná, Petra and Kollár, Peter and Fedr, Radek and Ešner, Milan and Jaroš, Josef and Hampl, Aleš and Krejčí, Lumír and Paruch, Kamil and Souček, Karel},
   article_location = {Philadelphia},
   article_number = {9},
   doi = {http://dx.doi.org/10.1158/1535-7163.MCT-17-0018},
   keywords = {Synthesis and Profiling of a Novel Potent Selective Inhibitor},
   language = {eng},
   issn = {1535-7163},
   journal = {Molecular Cancer Therapeutics},
   title = {Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation},
   url = {http://mct.aacrjournals.org/content/16/9/1831.full#ref-list-1},
   volume = {16},
   year = {2017}
}

TY  - JOUR
ID  - 1388764
AU  - Samadder, Pounami - Suchánková, Tereza - Hylse, Ondřej - Khirsariya, PrashantKumar - Nikulenkov, Fedor - Drápela, Stanislav - Straková, Nicol - Vaňhara, Petr - Vašíčková, Kateřina - Kolářová, Hana - Binó, Lucia - Bittová, Miroslava - Ovesná, Petra - Kollár, Peter - Fedr, Radek - Ešner, Milan - Jaroš, Josef - Hampl, Aleš - Krejčí, Lumír - Paruch, Kamil - Souček, Karel
PY  - 2017
TI  - Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation
JF  - Molecular Cancer Therapeutics
VL  - 16
IS  - 9
SP  - 1831-1842
EP  - 1831-1842
PB  - American Association for Cancer Research
SN  - 15357163
KW  - Synthesis and Profiling of a Novel Potent Selective Inhibitor
UR  - http://mct.aacrjournals.org/content/16/9/1831.full#ref-list-1
N2  - 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. CHK10s 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.
ER  -

SAMADDER, Pounami, Tereza SUCHÁNKOVÁ, Ondřej HYLSE, PrashantKumar KHIRSARIYA, Fedor NIKULENKOV, Stanislav DRÁPELA, Nicol STRAKOVÁ, Petr VAŇHARA, Kateřina VAŠÍČKOVÁ, Hana KOLÁŘOVÁ, Lucia BINÓ, Miroslava BITTOVÁ, Petra OVESNÁ, Peter KOLLÁR, Radek FEDR, Milan EŠNER, Josef JAROŠ, Aleš HAMPL, Lumír KREJČÍ, Kamil PARUCH and Karel SOUČEK. Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation. \textit{Molecular Cancer Therapeutics}. Philadelphia: American Association for Cancer Research, 2017, vol.~16, No~9, p.~1831-1842. ISSN~1535-7163. Available from: https://dx.doi.org/10.1158/1535-7163.MCT-17-0018.

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