A Casein kinase 1/Checkpoint kinase 1 pyrazolo-pyridine protein kinase inhibitor as novel activator of the p53 pathway

Anne-Sophie Huart; Barbara Saxty; Andy Merritt; Marta Nekulova; Stephen Lewis; Yide Huang; Borivoj Vojtesek; Catherine Kettleborough; Ted R Hupp

doi:10.1016/j.bmcl.2013.08.046

A Casein kinase 1/Checkpoint kinase 1 pyrazolo-pyridine protein kinase inhibitor as novel activator of the p53 pathway

Anne-Sophie Huart, Barbara Saxty, Andy Merritt, Marta Nekulova, Stephen Lewis, Yide Huang, Borivoj Vojtesek, Catherine Kettleborough, Ted R Hupp

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Reactivation of the wild-type p53 pathway is one key goal aimed at developing targeted therapeutics in the cancer research field. Although most p53 protein kinases form 'p53-activating' signals, there are few kinases whose action can contribute to the inhibition of p53, as Casein kinase 1 (CK1) and Checkpoint kinase 1 (CHK1). Here we report on a pyrazolo-pyridine analogue showing activity against both CK1 and CHK1 kinases that lead to p53 pathway stabilisation, thus having pharmacological similarities to the p53-activator Nutlin-3. These data demonstrate the emerging potential utility of multivalent kinase inhibitors.

Original language	English
Pages (from-to)	5578-5585
Number of pages	8
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	23
Issue number	20
DOIs	https://doi.org/10.1016/j.bmcl.2013.08.046
Publication status	Published - 15 Oct 2013

Keywords / Materials (for Non-textual outputs)

Kinase inhibitor
p53 Pathway activation
Casein kinase 1
Checkpoint kinase 1

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10.1016/j.bmcl.2013.08.046

http://www.sciencedirect.com/science/article/pii/S0960894X13009864

Cite this

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title = "A Casein kinase 1/Checkpoint kinase 1 pyrazolo-pyridine protein kinase inhibitor as novel activator of the p53 pathway",

abstract = "Reactivation of the wild-type p53 pathway is one key goal aimed at developing targeted therapeutics in the cancer research field. Although most p53 protein kinases form 'p53-activating' signals, there are few kinases whose action can contribute to the inhibition of p53, as Casein kinase 1 (CK1) and Checkpoint kinase 1 (CHK1). Here we report on a pyrazolo-pyridine analogue showing activity against both CK1 and CHK1 kinases that lead to p53 pathway stabilisation, thus having pharmacological similarities to the p53-activator Nutlin-3. These data demonstrate the emerging potential utility of multivalent kinase inhibitors.",

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language = "English",

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journal = "Bioorganic & Medicinal Chemistry Letters",

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T1 - A Casein kinase 1/Checkpoint kinase 1 pyrazolo-pyridine protein kinase inhibitor as novel activator of the p53 pathway

AU - Huart, Anne-Sophie

AU - Saxty, Barbara

AU - Merritt, Andy

AU - Nekulova, Marta

AU - Lewis, Stephen

AU - Huang, Yide

AU - Vojtesek, Borivoj

AU - Kettleborough, Catherine

AU - Hupp, Ted R

PY - 2013/10/15

Y1 - 2013/10/15

N2 - Reactivation of the wild-type p53 pathway is one key goal aimed at developing targeted therapeutics in the cancer research field. Although most p53 protein kinases form 'p53-activating' signals, there are few kinases whose action can contribute to the inhibition of p53, as Casein kinase 1 (CK1) and Checkpoint kinase 1 (CHK1). Here we report on a pyrazolo-pyridine analogue showing activity against both CK1 and CHK1 kinases that lead to p53 pathway stabilisation, thus having pharmacological similarities to the p53-activator Nutlin-3. These data demonstrate the emerging potential utility of multivalent kinase inhibitors.

AB - Reactivation of the wild-type p53 pathway is one key goal aimed at developing targeted therapeutics in the cancer research field. Although most p53 protein kinases form 'p53-activating' signals, there are few kinases whose action can contribute to the inhibition of p53, as Casein kinase 1 (CK1) and Checkpoint kinase 1 (CHK1). Here we report on a pyrazolo-pyridine analogue showing activity against both CK1 and CHK1 kinases that lead to p53 pathway stabilisation, thus having pharmacological similarities to the p53-activator Nutlin-3. These data demonstrate the emerging potential utility of multivalent kinase inhibitors.

KW - Kinase inhibitor

KW - p53 Pathway activation

KW - Casein kinase 1

KW - Checkpoint kinase 1

U2 - 10.1016/j.bmcl.2013.08.046

DO - 10.1016/j.bmcl.2013.08.046

M3 - Article

C2 - 24007918

SN - 0960-894X

VL - 23

SP - 5578

EP - 5585

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 20

ER -

A Casein kinase 1/Checkpoint kinase 1 pyrazolo-pyridine protein kinase inhibitor as novel activator of the p53 pathway

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

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