Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3

Laura A. T. Cleghorn; Andrew Woodland; Iain T. Collie; Leah S. Torrie; Neil Norcross; Torsten Luksch; Chido Mpamhanga; Roderick G. Walker; Jeremy C. Mottram; Ruth Brenk; Julie A. Frearson; Ian H. Gilbert; Paul G. Wyatt

doi:10.1002/cmdc.201100344

Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3

Laura A. T. Cleghorn
, Andrew Woodland
, Iain T. Collie
, Leah S. Torrie
, Neil Norcross
, Torsten Luksch
, Chido Mpamhanga
, Roderick G. Walker
, Jeremy C. Mottram
, Ruth Brenk
, Julie A. Frearson
, Ian H. Gilbert
, Paul G. Wyatt (Lead / Corresponding author)

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

49 Citations (Scopus)

7 Downloads (Pure)

Abstract

New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high-throughput screen of a focussed kinase set of similar to 3400 compounds to identify potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3-cyclin 6 complex. The aim of this study is to provide chemical validation that Leishmania CRK3-CYC6 is a drug target. Eight hit series were identified, of which four were followed up. The optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin dependent kinase CDK2.

Original language	English
Pages (from-to)	2214-2224
Number of pages	11
Journal	ChemMedChem
Volume	6
Issue number	12
DOIs	https://doi.org/10.1002/cmdc.201100344
Publication status	Published - 9 Dec 2011

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

CRK3
cyclin-dependent cdc2-related kinases
leishmaniasis
triazolopyridines
ureas
CYCLIN-DEPENDENT KINASE
TRYPANOSOMA-BRUCEI
3-AMINOPYRAZOLE INHIBITORS
ANTITUMOR AGENTS
DISCOVERY
MEXICANA
DISEASES

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10.1002/cmdc.201100344

http://ukpmc.ac.uk/articles/PMC3272345

Cite this

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title = "Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3",

abstract = "New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high-throughput screen of a focussed kinase set of similar to 3400 compounds to identify potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3-cyclin 6 complex. The aim of this study is to provide chemical validation that Leishmania CRK3-CYC6 is a drug target. Eight hit series were identified, of which four were followed up. The optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin dependent kinase CDK2.",

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author = "Cleghorn, \{Laura A. T.\} and Andrew Woodland and Collie, \{Iain T.\} and Torrie, \{Leah S.\} and Neil Norcross and Torsten Luksch and Chido Mpamhanga and Walker, \{Roderick G.\} and Mottram, \{Jeremy C.\} and Ruth Brenk and Frearson, \{Julie A.\} and Gilbert, \{Ian H.\} and Wyatt, \{Paul G.\}",

year = "2011",

month = dec,

day = "9",

doi = "10.1002/cmdc.201100344",

language = "English",

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T1 - Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3

AU - Cleghorn, Laura A. T.

AU - Woodland, Andrew

AU - Collie, Iain T.

AU - Torrie, Leah S.

AU - Norcross, Neil

AU - Luksch, Torsten

AU - Mpamhanga, Chido

AU - Walker, Roderick G.

AU - Mottram, Jeremy C.

AU - Brenk, Ruth

AU - Frearson, Julie A.

AU - Gilbert, Ian H.

AU - Wyatt, Paul G.

PY - 2011/12/9

Y1 - 2011/12/9

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AB - New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high-throughput screen of a focussed kinase set of similar to 3400 compounds to identify potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3-cyclin 6 complex. The aim of this study is to provide chemical validation that Leishmania CRK3-CYC6 is a drug target. Eight hit series were identified, of which four were followed up. The optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin dependent kinase CDK2.

KW - CRK3

KW - cyclin-dependent cdc2-related kinases

KW - leishmaniasis

KW - triazolopyridines

KW - ureas

KW - CYCLIN-DEPENDENT KINASE

KW - TRYPANOSOMA-BRUCEI

KW - 3-AMINOPYRAZOLE INHIBITORS

KW - ANTITUMOR AGENTS

KW - DISCOVERY

KW - MEXICANA

KW - DISEASES

UR - https://www.scopus.com/pages/publications/82955186879

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DO - 10.1002/cmdc.201100344

M3 - Article

C2 - 21913331

SN - 1860-7179

VL - 6

SP - 2214

EP - 2224

JO - ChemMedChem

JF - ChemMedChem

IS - 12

ER -

Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3

Abstract

UN SDGs

Keywords

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