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

47 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

Keywords

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

UN SDGs

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

Access to Document

10.1002/cmdc.201100344

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

Cite this

@article{da4a4674a064480d8ea707c732b55eed,

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.",

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

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",

volume = "6",

pages = "2214--2224",

journal = "ChemMedChem",

issn = "1860-7179",

publisher = "Wiley",

number = "12",

}

TY - JOUR

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

N2 - 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.

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 - http://www.scopus.com/inward/record.url?scp=82955186879&partnerID=8YFLogxK

U2 - 10.1002/cmdc.201100344

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

Keywords

UN SDGs

Access to Document

Other files and links

Embargoed Document

Fingerprint

Cite this