-
Something wrong with this record ?
Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation
P. Samadder, T. Suchánková, O. Hylse, P. Khirsariya, F. Nikulenkov, S. Drápela, N. Straková, P. Vaňhara, K. Vašíčková, H. Kolářová, L. Binó, M. Bittová, P. Ovesná, P. Kollár, R. Fedr, M. Ešner, J. Jaroš, A. Hampl, L. Krejčí, K. Paruch, K. Souček,
Language English Country United States
Document type Journal Article
Grant support
NV15-33999A
MZ0
CEP Register
Digital library NLK
Full text - Article
Source
NLK
Free Medical Journals
from 2001 to 1 year ago
Open Access Digital Library
from 2001-11-01
Open Access Digital Library
from 2001-11-01
- MeSH
- Apoptosis drug effects MeSH
- Biomarkers MeSH
- Cell Cycle drug effects MeSH
- Checkpoint Kinase 1 antagonists & inhibitors MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Dealkylation drug effects MeSH
- Protein Kinase Inhibitors chemical synthesis pharmacology MeSH
- Cell Cycle Checkpoints drug effects MeSH
- Humans MeSH
- Methylation MeSH
- Disease Models, Animal MeSH
- Molecular Structure MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Antineoplastic Agents chemical synthesis pharmacology MeSH
- Pyrazoles pharmacology MeSH
- Pyrimidines pharmacology MeSH
- Dose-Response Relationship, Drug MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
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.
Cellular Imaging Core Facility CELLIM CEITEC Masaryk University Brno Czech Republic
Department of Chemistry CZ Openscreen Faculty of Science Masaryk University Brno Czech Republic
Department of Cytokinetics Institute of Biophysics CAS Brno Czech Republic
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc18024934
- 003
- CZ-PrNML
- 005
- 20241217090112.0
- 007
- ta
- 008
- 180709s2017 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1158/1535-7163.MCT-17-0018 $2 doi
- 035 __
- $a (PubMed)28619751
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Samadder, Pounami $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. National Centre for Biomolecular Research, Masaryk University, Brno, Czech Republic. International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic.
- 245 10
- $a Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation / $c P. Samadder, T. Suchánková, O. Hylse, P. Khirsariya, F. Nikulenkov, S. Drápela, N. Straková, P. Vaňhara, K. Vašíčková, H. Kolářová, L. Binó, M. Bittová, P. Ovesná, P. Kollár, R. Fedr, M. Ešner, J. Jaroš, A. Hampl, L. Krejčí, K. Paruch, K. Souček,
- 520 9_
- $a 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.
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a protinádorové látky $x chemická syntéza $x farmakologie $7 D000970
- 650 _2
- $a apoptóza $x účinky léků $7 D017209
- 650 _2
- $a biologické markery $7 D015415
- 650 _2
- $a buněčný cyklus $x účinky léků $7 D002453
- 650 _2
- $a kontrolní body buněčného cyklu $x účinky léků $7 D059447
- 650 _2
- $a nádorové buněčné linie $7 D045744
- 650 _2
- $a checkpoint kinasa 1 $x antagonisté a inhibitory $7 D000071877
- 650 _2
- $a dealkylace $x účinky léků $7 D003640
- 650 _2
- $a modely nemocí na zvířatech $7 D004195
- 650 _2
- $a vztah mezi dávkou a účinkem léčiva $7 D004305
- 650 _2
- $a chemorezistence $x účinky léků $7 D019008
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a metylace $7 D008745
- 650 _2
- $a myši $7 D051379
- 650 _2
- $a molekulární struktura $7 D015394
- 650 _2
- $a inhibitory proteinkinas $x chemická syntéza $x farmakologie $7 D047428
- 650 _2
- $a pyrazoly $x farmakologie $7 D011720
- 650 _2
- $a pyrimidiny $x farmakologie $7 D011743
- 650 _2
- $a xenogenní modely - testy protinádorové aktivity $7 D023041
- 655 _2
- $a časopisecké články $7 D016428
- 700 1_
- $a Suchánková, Tereza $u Department of Cytokinetics, Institute of Biophysics CAS, Brno, Czech Republic.
- 700 1_
- $a Hylse, Ondřej $u Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech Republic.
- 700 1_
- $a Khirsariya, Prashant $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic. Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech Republic.
- 700 1_
- $a Nikulenkov, Fedor $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic.
- 700 1_
- $a Drápela, Stanislav $u Department of Cytokinetics, Institute of Biophysics CAS, Brno, Czech Republic. $7 xx0280838
- 700 1_
- $a Straková, Nicol $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic. Department of Cytokinetics, Institute of Biophysics CAS, Brno, Czech Republic.
- 700 1_
- $a Vaňhara, Petr $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic. Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic.
- 700 1_
- $a Vašíčková, Kateřina $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic. Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic.
- 700 1_
- $a Kolářová, Hana $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. National Centre for Biomolecular Research, Masaryk University, Brno, Czech Republic. International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic.
- 700 1_
- $a Binó, Lucia $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic. Department of Cytokinetics, Institute of Biophysics CAS, Brno, Czech Republic. $7 xx0326742
- 700 1_
- $a Bittová, Miroslava $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic. Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech Republic.
- 700 1_
- $a Ovesná, Petra $u Department of Cytokinetics, Institute of Biophysics CAS, Brno, Czech Republic. Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic.
- 700 1_
- $a Kollár, Peter $u Cellular Imaging Core Facility - CELLIM, CEITEC Masaryk University, Brno, Czech Republic.
- 700 1_
- $a Fedr, Radek $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic. Department of Cytokinetics, Institute of Biophysics CAS, Brno, Czech Republic.
- 700 1_
- $a Ešner, Milan $u Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic. Cellular Imaging Core Facility - CELLIM, CEITEC Masaryk University, Brno, Czech Republic.
- 700 1_
- $a Jaroš, Josef $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic. Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic.
- 700 1_
- $a Hampl, Aleš $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic. Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic.
- 700 1_
- $a Krejčí, Lumír $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. lkrejci@chemi.muni.cz paruch@sci.muni.cz ksoucek@ibp.cz. National Centre for Biomolecular Research, Masaryk University, Brno, Czech Republic. International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic.
- 700 1_
- $a Paruch, Kamil $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic. lkrejci@chemi.muni.cz paruch@sci.muni.cz ksoucek@ibp.cz. Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech Republic.
- 700 1_
- $a Souček, Karel $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Brno, Czech Republic. lkrejci@chemi.muni.cz paruch@sci.muni.cz ksoucek@ibp.cz. Department of Cytokinetics, Institute of Biophysics CAS, Brno, Czech Republic. Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
- 773 0_
- $w MED00006616 $t Molecular cancer therapeutics $x 1538-8514 $g Roč. 16, č. 9 (2017), s. 1831-1842
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/28619751 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y a $z 0
- 990 __
- $a 20180709 $b ABA008
- 991 __
- $a 20241217090108 $b ABA008
- 999 __
- $a ok $b bmc $g 1317065 $s 1021855
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2017 $b 16 $c 9 $d 1831-1842 $e 20170615 $i 1538-8514 $m Molecular cancer therapeutics $n Mol Cancer Ther $x MED00006616
- GRA __
- $a NV15-33999A $p MZ0
- LZP __
- $a Pubmed-20180709
