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.

Základní údaje

Originální název

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

Autoři

SAMADDER, Pounami (356 Indie, domácí), Tereza SUCHÁNKOVÁ (203 Česká republika), Ondřej HYLSE (203 Česká republika, domácí), PrashantKumar KHIRSARIYA (356 Indie, domácí), Fedor NIKULENKOV (643 Rusko, domácí), Stanislav DRÁPELA (203 Česká republika), Nicol STRAKOVÁ (203 Česká republika), Petr VAŇHARA (203 Česká republika, domácí), Kateřina VAŠÍČKOVÁ (203 Česká republika, domácí), Hana KOLÁŘOVÁ (203 Česká republika, domácí), Lucia BINÓ (703 Slovensko), Miroslava BITTOVÁ (203 Česká republika, domácí), Petra OVESNÁ (203 Česká republika, domácí), Peter KOLLÁR (203 Česká republika), Radek FEDR (203 Česká republika), Milan EŠNER (203 Česká republika, domácí), Josef JAROŠ (203 Česká republika, domácí), Aleš HAMPL (203 Česká republika, domácí), Lumír KREJČÍ (203 Česká republika, domácí), Kamil PARUCH (203 Česká republika, domácí) a Karel SOUČEK (203 Česká republika, domácí)

Vydání

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

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 5.365

Kód RIV

RIV/00216224:14110/17:00095657

Organizační jednotka

Lékařská fakulta

DOI

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

UT WoS

000409550300009

Klíčová slova anglicky

Synthesis and Profiling of a Novel Potent Selective Inhibitor

Štítky

EL OK, podil

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 18. 3. 2018 17:15, Soňa Böhmová

Anotace

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.

Návaznosti

EE2.3.20.0185, projekt VaV

Název: Centrum analýz a modelování tkání a orgánů

LM2015063, projekt VaV

Název: Národní infrastruktura chemické biologie (Akronym: CZ-OPENSCREEN)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CZ-OPENSCREEN: National Infrastructure for Chemical Biology

NV15-33999A, projekt VaV

Název: 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 a 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, roč. 16, č. 9, s. 1831-1842. ISSN 1535-7163. Dostupné z: 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 a 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, roč.~16, č.~9, s.~1831-1842. ISSN~1535-7163. Dostupné z: https://dx.doi.org/10.1158/1535-7163.MCT-17-0018.

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