Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3. / Cleghorn, Laura A. T.; Woodland, Andrew; Collie, Iain T.; Torrie, Leah S.; Norcross, Neil; Luksch, Torsten; Mpamhanga, Chido; Walker, Roderick G.; Mottram, Jeremy C.; Brenk, Ruth; Frearson, Julie A.; Gilbert, Ian H.; Wyatt, Paul G.
In: ChemMedChem, Vol. 6, No. 12, 09.12.2011, p. 2214-2224.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3
A1 - Cleghorn,Laura A. T.
A1 - Woodland,Andrew
A1 - Collie,Iain T.
A1 - Torrie,Leah S.
A1 - Norcross,Neil
A1 - Luksch,Torsten
A1 - Mpamhanga,Chido
A1 - Walker,Roderick G.
A1 - Mottram,Jeremy C.
A1 - Brenk,Ruth
A1 - Frearson,Julie A.
A1 - Gilbert,Ian H.
A1 - Wyatt,Paul G.
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 - <p>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.</p>
AB - <p>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.</p>
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://ukpmc.ac.uk/articles/PMC3272345
U2 - 10.1002/cmdc.201100344
DO - 10.1002/cmdc.201100344
M1 - Article
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 12
VL - 6
SP - 2214
EP - 2224
ER -
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