Synthesis, biological properties and structural study of new halogenated azolo[4,5-b]pyridines as inhibitors of CK2 kinase

K Chojnacki; Christine Toelzer; et al.

doi:10.1016/j.bioorg.2020.104502

Synthesis, biological properties and structural study of new halogenated azolo[4,5-b]pyridines as inhibitors of CK2 kinase

K Chojnacki^*, Christine Toelzer, et al.

^*Corresponding author for this work

School of Biochemistry

Research output: Contribution to journal › Article (Academic Journal) › peer-review

9 Citations (Scopus)

Abstract

The new halogenated 1H-triazolo[4,5-b]pyridines and 1H-imidazo[4,5-b]pyridines were synthesised as analogues of known CK2 inhibitors: 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) and 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi). Their influence on the activity of recombinant human CK2α, CK2α’ and PIM1 kinases was determined. The most active inhibitors were di- and trihalogenated 1H-triazolo[4,5-b]pyridines (4a, 5a and 10a) with IC50 values 2.56, 3.82 and 3.26 μM respectively for CK2α. Furthermore, effect on viability of cancer cell lines MCF-7 (human breast adenocarcinoma) and CCRF-CEM (T lymphoblast leukemia) of all final compounds was evaluated. Finally, three crystal structures of complexes of CK2α1-335 with inhibitors 4a, 5a and 10a were obtained. In addition, new protocol was used to obtain high-resolution crystal structures of CK2α’Cys336Ser in complex with four inhibitors (4a, 5a, 5b, 10a).

Original language	English
Article number	104502
Number of pages	12
Journal	Bioorganic chemistry
Volume	106
Early online date	24 Nov 2020
DOIs	https://doi.org/10.1016/j.bioorg.2020.104502
Publication status	Published - 1 Jan 2021

Bibliographical note

Funding Information:
This work was supported by Warsaw University of Technology and by the Deutsche Forschungsgemeinschaft (grant NI 643/4-2 and project B07 of SFB635). We would like to thank Pawe? Borowiecki from Warsaw University of Technology, Faculty of Chemistry for HPLC analyses. We thank the staff of the beamline X06DA at the SLS (Villigen, Switzerland) and of the beamlines ID23-2 and ID29 at the ESRF (Grenoble, France) for support with X-ray data collection. We are grateful to Professor Ulrich Baumann (University of Cologne) for access to protein crystallography infrastructure and continuous support.

Funding Information:
This work was supported by Warsaw University of Technology and by the Deutsche Forschungsgemeinschaft (grant NI 643/4-2 and project B07 of SFB635). We would like to thank Paweł Borowiecki from Warsaw University of Technology, Faculty of Chemistry for HPLC analyses.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

Casein Kinase CK2
Protein Kinase PIM1
Structural study
ATP-Competitive inhibitors

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title = "Synthesis, biological properties and structural study of new halogenated azolo[4,5-b]pyridines as inhibitors of CK2 kinase",

abstract = "The new halogenated 1H-triazolo[4,5-b]pyridines and 1H-imidazo[4,5-b]pyridines were synthesised as analogues of known CK2 inhibitors: 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) and 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi). Their influence on the activity of recombinant human CK2α, CK2α{\textquoteright} and PIM1 kinases was determined. The most active inhibitors were di- and trihalogenated 1H-triazolo[4,5-b]pyridines (4a, 5a and 10a) with IC50 values 2.56, 3.82 and 3.26 μM respectively for CK2α. Furthermore, effect on viability of cancer cell lines MCF-7 (human breast adenocarcinoma) and CCRF-CEM (T lymphoblast leukemia) of all final compounds was evaluated. Finally, three crystal structures of complexes of CK2α1-335 with inhibitors 4a, 5a and 10a were obtained. In addition, new protocol was used to obtain high-resolution crystal structures of CK2α{\textquoteright}Cys336Ser in complex with four inhibitors (4a, 5a, 5b, 10a).",

keywords = "Casein Kinase CK2, Protein Kinase PIM1, Structural study, ATP-Competitive inhibitors",

author = "K Chojnacki and Christine Toelzer and {et al.}",

note = "Funding Information: This work was supported by Warsaw University of Technology and by the Deutsche Forschungsgemeinschaft (grant NI 643/4-2 and project B07 of SFB635). We would like to thank Pawe? Borowiecki from Warsaw University of Technology, Faculty of Chemistry for HPLC analyses. We thank the staff of the beamline X06DA at the SLS (Villigen, Switzerland) and of the beamlines ID23-2 and ID29 at the ESRF (Grenoble, France) for support with X-ray data collection. We are grateful to Professor Ulrich Baumann (University of Cologne) for access to protein crystallography infrastructure and continuous support. Funding Information: This work was supported by Warsaw University of Technology and by the Deutsche Forschungsgemeinschaft (grant NI 643/4-2 and project B07 of SFB635). We would like to thank Pawe{\l} Borowiecki from Warsaw University of Technology, Faculty of Chemistry for HPLC analyses. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

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doi = "10.1016/j.bioorg.2020.104502",

language = "English",

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T1 - Synthesis, biological properties and structural study of new halogenated azolo[4,5-b]pyridines as inhibitors of CK2 kinase

AU - Chojnacki, K

AU - Toelzer, Christine

AU - et al.

N1 - Funding Information: This work was supported by Warsaw University of Technology and by the Deutsche Forschungsgemeinschaft (grant NI 643/4-2 and project B07 of SFB635). We would like to thank Pawe? Borowiecki from Warsaw University of Technology, Faculty of Chemistry for HPLC analyses. We thank the staff of the beamline X06DA at the SLS (Villigen, Switzerland) and of the beamlines ID23-2 and ID29 at the ESRF (Grenoble, France) for support with X-ray data collection. We are grateful to Professor Ulrich Baumann (University of Cologne) for access to protein crystallography infrastructure and continuous support. Funding Information: This work was supported by Warsaw University of Technology and by the Deutsche Forschungsgemeinschaft (grant NI 643/4-2 and project B07 of SFB635). We would like to thank Paweł Borowiecki from Warsaw University of Technology, Faculty of Chemistry for HPLC analyses. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2021/1/1

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N2 - The new halogenated 1H-triazolo[4,5-b]pyridines and 1H-imidazo[4,5-b]pyridines were synthesised as analogues of known CK2 inhibitors: 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) and 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi). Their influence on the activity of recombinant human CK2α, CK2α’ and PIM1 kinases was determined. The most active inhibitors were di- and trihalogenated 1H-triazolo[4,5-b]pyridines (4a, 5a and 10a) with IC50 values 2.56, 3.82 and 3.26 μM respectively for CK2α. Furthermore, effect on viability of cancer cell lines MCF-7 (human breast adenocarcinoma) and CCRF-CEM (T lymphoblast leukemia) of all final compounds was evaluated. Finally, three crystal structures of complexes of CK2α1-335 with inhibitors 4a, 5a and 10a were obtained. In addition, new protocol was used to obtain high-resolution crystal structures of CK2α’Cys336Ser in complex with four inhibitors (4a, 5a, 5b, 10a).

AB - The new halogenated 1H-triazolo[4,5-b]pyridines and 1H-imidazo[4,5-b]pyridines were synthesised as analogues of known CK2 inhibitors: 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) and 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi). Their influence on the activity of recombinant human CK2α, CK2α’ and PIM1 kinases was determined. The most active inhibitors were di- and trihalogenated 1H-triazolo[4,5-b]pyridines (4a, 5a and 10a) with IC50 values 2.56, 3.82 and 3.26 μM respectively for CK2α. Furthermore, effect on viability of cancer cell lines MCF-7 (human breast adenocarcinoma) and CCRF-CEM (T lymphoblast leukemia) of all final compounds was evaluated. Finally, three crystal structures of complexes of CK2α1-335 with inhibitors 4a, 5a and 10a were obtained. In addition, new protocol was used to obtain high-resolution crystal structures of CK2α’Cys336Ser in complex with four inhibitors (4a, 5a, 5b, 10a).

KW - Casein Kinase CK2

KW - Protein Kinase PIM1

KW - Structural study

KW - ATP-Competitive inhibitors

U2 - 10.1016/j.bioorg.2020.104502

DO - 10.1016/j.bioorg.2020.104502

M3 - Article (Academic Journal)

C2 - 33317841

SN - 0045-2068

VL - 106

JO - Bioorganic chemistry

JF - Bioorganic chemistry

M1 - 104502

ER -

Synthesis, biological properties and structural study of new halogenated azolo[4,5-b]pyridines as inhibitors of CK2 kinase

Abstract

Bibliographical note

Keywords

UN SDGs

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