Novel CHK1 inhibitor MU380 exhibits significant single-agent
activity in TP53-mutated chronic lymphocytic leukemia cells

J 2019

Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells

BOUDNÝ, Miroslav, Jana ZEMANOVÁ, PrashantKumar KHIRSARIYA, Marek BORSKÝ, Jan VERNER et. al.

Basic information

Original name

Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells

Authors

BOUDNÝ, Miroslav (203 Czech Republic, belonging to the institution), Jana ZEMANOVÁ (203 Czech Republic, belonging to the institution), PrashantKumar KHIRSARIYA (356 India, belonging to the institution), Marek BORSKÝ (203 Czech Republic, belonging to the institution), Jan VERNER (203 Czech Republic, belonging to the institution), Jana ČERNÁ (203 Czech Republic, belonging to the institution), Alexandra OLTOVÁ (203 Czech Republic, belonging to the institution), Václav ŠEDA (203 Czech Republic, belonging to the institution), Marek MRÁZ (203 Czech Republic, belonging to the institution), Josef JAROŠ (203 Czech Republic, belonging to the institution), Zuzana JAŠKOVÁ (703 Slovakia, belonging to the institution), Michaela ŠPUNAROVÁ (203 Czech Republic, belonging to the institution), Yvona BRYCHTOVÁ (203 Czech Republic, belonging to the institution), Karel SOUČEK (203 Czech Republic, belonging to the institution), Stanislav DRÁPELA (203 Czech Republic, belonging to the institution), Marie KAŠPÁRKOVÁ (203 Czech Republic, belonging to the institution), Jiří MAYER (203 Czech Republic, belonging to the institution), Kamil PARUCH (203 Czech Republic, belonging to the institution) and Martin TRBUŠEK (203 Czech Republic, guarantor, belonging to the institution)

Edition

Haematologica, PAVIA, FERRATA STORTI FOUNDATION, 2019, 0390-6078

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30205 Hematology

Country of publisher

Italy

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 7.116

RIV identification code

RIV/00216224:14110/19:00108541

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.3324/haematol.2018.203430

UT WoS

000499687600029

Keywords in English

IN-VITRO; KINASE; CLL; PROLIFERATION; ACTIVATION; MUTATIONS; LETHALITY; OUTCOMES; IMPACT; MODEL

Abstract

V originále

Introduction of small-molecule inhibitors of B-cell receptor signaling and BCL2 protein significantly improves therapeutic options in chronic lymphocytic leukemia. However, some patients suffer from adverse effects mandating treatment discontinuation, and cases with TP53 defects more frequently experience early progression of the disease. Development of alternative therapeutic approaches is, therefore, of critical importance. Here we report details of the anti-chronic lymphocytic leukemia single-agent activity of MU380, our recently identified potent, selective, and metabolically robust inhibitor of checkpoint kinase 1. We also describe a newly developed enantioselective synthesis of MU380, which allows preparation of gram quantities of the substance. Checkpoint kinase 1 is a master regulator of replication operating primarily in intra-S and G(2)/M cell cycle checkpoints. Initially tested in leukemia and lymphoma cell lines, MU380 significantly potentiated efficacy of gemcitabine, a clinically used inducer of replication stress. Moreover, MU380 manifested substantial single-agent activity in both TP53-wild type and TP53-mutated leukemia and lymphoma cell lines. In chronic lymphocytic leukemia-derived cell lines MEC-1, MEC-2 (both TP53-mut), and OSU-CLL (TP53-wt) the inhibitor impaired cell cycle progression and induced apoptosis. In primary clinical samples, MU380 used as a single-agent noticeably reduced the viability of unstimulated chronic lymphocytic leukemia cells as well as those induced to proliferate by anti-CD40/IL-4 stimuli. In both cases, effects were comparable in samples harboring p53 pathway dysfunction (TP53 mutations or ATM mutations) and TP53-wt/ATM-wt cells. Lastly, MU380 also exhibited significant in vivo activity in a xenotransplant mouse model (immunodeficient strain NOD-scid IL2R gamma(null)) where it efficiently suppressed growth of subcutaneous tumors generated from MEC-1 cells.

Links

LM2015063, research and development project

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

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

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

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

MUNI/A/1105/2018, interní kód MU

Name: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VI (Acronym: VýDiTeHeMA VI)

Investor: Masaryk University, Category A

NV15-33999A, research and development project

Name: Vývoj nových nízkomolekulárních protinádorových léčiv na principu syntetické letality

Citovat

BOUDNÝ, Miroslav, Jana ZEMANOVÁ, PrashantKumar KHIRSARIYA, Marek BORSKÝ, Jan VERNER, Jana ČERNÁ, Alexandra OLTOVÁ, Václav ŠEDA, Marek MRÁZ, Josef JAROŠ, Zuzana JAŠKOVÁ, Michaela ŠPUNAROVÁ, Yvona BRYCHTOVÁ, Karel SOUČEK, Stanislav DRÁPELA, Marie KAŠPÁRKOVÁ, Jiří MAYER, Kamil PARUCH and Martin TRBUŠEK. Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells. Haematologica. PAVIA: FERRATA STORTI FOUNDATION, 2019, vol. 104, No 12, p. 2443-2455. ISSN 0390-6078. Available from: https://dx.doi.org/10.3324/haematol.2018.203430.

@article{1582239,
   author = {Boudný, Miroslav and Zemanová, Jana and Khirsariya, PrashantKumar and Borský, Marek and Verner, Jan and Černá, Jana and Oltová, Alexandra and Šeda, Václav and Mráz, Marek and Jaroš, Josef and Jašková, Zuzana and Špunarová, Michaela and Brychtová, Yvona and Souček, Karel and Drápela, Stanislav and Kašpárková, Marie and Mayer, Jiří and Paruch, Kamil and Trbušek, Martin},
   article_location = {PAVIA},
   article_number = {12},
   doi = {http://dx.doi.org/10.3324/haematol.2018.203430},
   keywords = {IN-VITRO; KINASE; CLL; PROLIFERATION; ACTIVATION; MUTATIONS; LETHALITY; OUTCOMES; IMPACT; MODEL},
   language = {eng},
   issn = {0390-6078},
   journal = {Haematologica},
   title = {Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells},
   url = {http://www.haematologica.org/content/104/12/2443},
   volume = {104},
   year = {2019}
}

TY  - JOUR
ID  - 1582239
AU  - Boudný, Miroslav - Zemanová, Jana - Khirsariya, PrashantKumar - Borský, Marek - Verner, Jan - Černá, Jana - Oltová, Alexandra - Šeda, Václav - Mráz, Marek - Jaroš, Josef - Jašková, Zuzana - Špunarová, Michaela - Brychtová, Yvona - Souček, Karel - Drápela, Stanislav - Kašpárková, Marie - Mayer, Jiří - Paruch, Kamil - Trbušek, Martin
PY  - 2019
TI  - Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells
JF  - Haematologica
VL  - 104
IS  - 12
SP  - 2443-2455
EP  - 2443-2455
PB  - FERRATA STORTI FOUNDATION
SN  - 03906078
KW  - IN-VITRO
KW  - KINASE
KW  - CLL
KW  - PROLIFERATION
KW  - ACTIVATION
KW  - MUTATIONS
KW  - LETHALITY
KW  - OUTCOMES
KW  - IMPACT
KW  - MODEL
UR  - http://www.haematologica.org/content/104/12/2443
L2  - http://www.haematologica.org/content/104/12/2443
N2  - Introduction of small-molecule inhibitors of B-cell receptor signaling and BCL2 protein significantly improves therapeutic options in chronic lymphocytic leukemia. However, some patients suffer from adverse effects mandating treatment discontinuation, and cases with TP53 defects more frequently experience early progression of the disease. Development of alternative therapeutic approaches is, therefore, of critical importance. Here we report details of the anti-chronic lymphocytic leukemia single-agent activity of MU380, our recently identified potent, selective, and metabolically robust inhibitor of checkpoint kinase 1. We also describe a newly developed enantioselective synthesis of MU380, which allows preparation of gram quantities of the substance. Checkpoint kinase 1 is a master regulator of replication operating primarily in intra-S and G(2)/M cell cycle checkpoints. Initially tested in leukemia and lymphoma cell lines, MU380 significantly potentiated efficacy of gemcitabine, a clinically used inducer of replication stress. Moreover, MU380 manifested substantial single-agent activity in both TP53-wild type and TP53-mutated leukemia and lymphoma cell lines. In chronic lymphocytic leukemia-derived cell lines MEC-1, MEC-2 (both TP53-mut), and OSU-CLL (TP53-wt) the inhibitor impaired cell cycle progression and induced apoptosis. In primary clinical samples, MU380 used as a single-agent noticeably reduced the viability of unstimulated chronic lymphocytic leukemia cells as well as those induced to proliferate by anti-CD40/IL-4 stimuli. In both cases, effects were comparable in samples harboring p53 pathway dysfunction (TP53 mutations or ATM mutations) and TP53-wt/ATM-wt cells. Lastly, MU380 also exhibited significant in vivo activity in a xenotransplant mouse model (immunodeficient strain NOD-scid IL2R gamma(null)) where it efficiently suppressed growth of subcutaneous tumors generated from MEC-1 cells.
ER  -

BOUDNÝ, Miroslav, Jana ZEMANOVÁ, PrashantKumar KHIRSARIYA, Marek BORSKÝ, Jan VERNER, Jana ČERNÁ, Alexandra OLTOVÁ, Václav ŠEDA, Marek MRÁZ, Josef JAROŠ, Zuzana JAŠKOVÁ, Michaela ŠPUNAROVÁ, Yvona BRYCHTOVÁ, Karel SOUČEK, Stanislav DRÁPELA, Marie KAŠPÁRKOVÁ, Jiří MAYER, Kamil PARUCH and Martin TRBUŠEK. Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells. \textit{Haematologica}. PAVIA: FERRATA STORTI FOUNDATION, 2019, vol.~104, No~12, p.~2443-2455. ISSN~0390-6078. Available from: https://dx.doi.org/10.3324/haematol.2018.203430.

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