Repositioning of a diaminothiazole series confirmed to target the cyclin-dependent kinase CRK12 for use in the treatment of African animal trypanosomiasis

Alasdair Smith; Richard Wall; Stephen Patterson; Tim Rowan; Eva Rico Vidal; Laste Stojanovski; Margaret Huggett; Shahienaz Hampton; Michael G. Thomas; Victoriano Corpas Lopez; Kirsten Gillingwater; Jeff Duke; Grant Napier; Rosemary Peter; Hervé S. Vitouley; Justin Harrison; Rachel Milne; Laura Jeacock; Nicola Baker; Susan Davis; Frederick Simeons; Jennifer Riley; David Horn; Reto Brun; Fabio Zuccotto; Michael J. Witty; Susan Wyllie; Kevin D. Read; Ian H. Gilbert

doi:10.1021/acs.jmedchem.1c02104

Repositioning of a diaminothiazole series confirmed to target the cyclin-dependent kinase CRK12 for use in the treatment of African animal trypanosomiasis

Alasdair Smith, Richard Wall, Stephen Patterson, Tim Rowan, Eva Rico Vidal, Laste Stojanovski, Margaret Huggett, Shahienaz Hampton, Michael G. Thomas, Victoriano Corpas Lopez, Kirsten Gillingwater, Jeff Duke, Grant Napier, Rosemary Peter, Hervé S. Vitouley, Justin Harrison, Rachel Milne, Laura Jeacock, Nicola Baker, Susan DavisFrederick Simeons, Jennifer Riley, David Horn, Reto Brun, Fabio Zuccotto, Michael J. Witty, Susan Wyllie (Lead / Corresponding author), Kevin D. Read (Lead / Corresponding author), Ian H. Gilbert (Lead / Corresponding author)

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Abstract

African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites Trypanosoma congolense and Trypanosoma vivax, is a major problem in cattle and other livestocks in sub-Saharan Africa. Current treatments are threatened by the emergence of drug resistance and there is an urgent need for new, effective drugs. Here, we report the repositioning of a compound series initially developed for the treatment of human African trypanosomiasis. A medicinal chemistry program, focused on deriving more soluble analogues, led to development of a lead compound capable of curing cattle infected with both T. congolense and T. vivax via intravenous dosing. Further optimization has the potential to yield a single-dose intramuscular treatment for this disease. Comprehensive mode of action studies revealed that the molecular target of this promising compound and related analogues is the cyclin-dependent kinase CRK12.

Original language	English
Pages (from-to)	5606-5624
Number of pages	19
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	7
Early online date	18 Mar 2022
DOIs	https://doi.org/10.1021/acs.jmedchem.1c02104
Publication status	Published - 14 Apr 2022

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine

UN SDGs

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

Access to Document

10.1021/acs.jmedchem.1c02104Licence: CC BY

Final Published VersionFinal published version, 2.67 MBLicence: CC BY
Supporting InformationOther version, 2.17 MB

Cite this

Smith, A., Wall, R., Patterson, S., Rowan, T., Rico Vidal, E., Stojanovski, L., Huggett, M., Hampton, S., Thomas, M. G., Corpas Lopez, V., Gillingwater, K., Duke, J., Napier, G., Peter, R., Vitouley, H. S., Harrison, J., Milne, R., Jeacock, L., Baker, N., ... Gilbert, I. H. (2022). Repositioning of a diaminothiazole series confirmed to target the cyclin-dependent kinase CRK12 for use in the treatment of African animal trypanosomiasis. Journal of Medicinal Chemistry, 65(7), 5606-5624. https://doi.org/10.1021/acs.jmedchem.1c02104

@article{02646016eb1447c6bf418c19913b3e44,

title = "Repositioning of a diaminothiazole series confirmed to target the cyclin-dependent kinase CRK12 for use in the treatment of African animal trypanosomiasis",

abstract = "African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites Trypanosoma congolense and Trypanosoma vivax, is a major problem in cattle and other livestocks in sub-Saharan Africa. Current treatments are threatened by the emergence of drug resistance and there is an urgent need for new, effective drugs. Here, we report the repositioning of a compound series initially developed for the treatment of human African trypanosomiasis. A medicinal chemistry program, focused on deriving more soluble analogues, led to development of a lead compound capable of curing cattle infected with both T. congolense and T. vivax via intravenous dosing. Further optimization has the potential to yield a single-dose intramuscular treatment for this disease. Comprehensive mode of action studies revealed that the molecular target of this promising compound and related analogues is the cyclin-dependent kinase CRK12.",

author = "Alasdair Smith and Richard Wall and Stephen Patterson and Tim Rowan and {Rico Vidal}, Eva and Laste Stojanovski and Margaret Huggett and Shahienaz Hampton and Thomas, {Michael G.} and {Corpas Lopez}, Victoriano and Kirsten Gillingwater and Jeff Duke and Grant Napier and Rosemary Peter and Vitouley, {Herv{\'e} S.} and Justin Harrison and Rachel Milne and Laura Jeacock and Nicola Baker and Susan Davis and Frederick Simeons and Jennifer Riley and David Horn and Reto Brun and Fabio Zuccotto and Witty, {Michael J.} and Susan Wyllie and Read, {Kevin D.} and Gilbert, {Ian H.}",

note = "Funding Information: This work is based on research funded in part by the Bill & Melinda Gates Foundation (Investment ID OPP1093639); with UK aid from the UK Government (Project 202040) through GALVmed; and Wellcome through a Pathfinder Award (103127, KDR, IHG); a Wellcome Strategic Award to the Division of Biological Chemistry and Drug Discovery (100476, IHG); Wellcome awards for funding of the Mode of Action group (105021 and 218448, SW, IHG, DH).",

year = "2022",

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doi = "10.1021/acs.jmedchem.1c02104",

language = "English",

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Smith, A, Wall, R , Patterson, S, Rowan, T, Rico Vidal, E, Stojanovski, L, Huggett, M, Hampton, S, Thomas, MG , Corpas Lopez, V, Gillingwater, K, Duke, J, Napier, G, Peter, R, Vitouley, HS, Harrison, J , Milne, R, Jeacock, L, Baker, N, Davis, S , Simeons, F , Riley, J , Horn, D, Brun, R, Zuccotto, F, Witty, MJ, Wyllie, S , Read, KD & Gilbert, IH 2022, 'Repositioning of a diaminothiazole series confirmed to target the cyclin-dependent kinase CRK12 for use in the treatment of African animal trypanosomiasis', Journal of Medicinal Chemistry, vol. 65, no. 7, pp. 5606-5624. https://doi.org/10.1021/acs.jmedchem.1c02104

TY - JOUR

T1 - Repositioning of a diaminothiazole series confirmed to target the cyclin-dependent kinase CRK12 for use in the treatment of African animal trypanosomiasis

AU - Smith, Alasdair

AU - Wall, Richard

AU - Patterson, Stephen

AU - Rowan, Tim

AU - Rico Vidal, Eva

AU - Stojanovski, Laste

AU - Huggett, Margaret

AU - Hampton, Shahienaz

AU - Thomas, Michael G.

AU - Corpas Lopez, Victoriano

AU - Gillingwater, Kirsten

AU - Duke, Jeff

AU - Napier, Grant

AU - Peter, Rosemary

AU - Vitouley, Hervé S.

AU - Harrison, Justin

AU - Milne, Rachel

AU - Jeacock, Laura

AU - Baker, Nicola

AU - Davis, Susan

AU - Simeons, Frederick

AU - Riley, Jennifer

AU - Horn, David

AU - Brun, Reto

AU - Zuccotto, Fabio

AU - Witty, Michael J.

AU - Wyllie, Susan

AU - Read, Kevin D.

AU - Gilbert, Ian H.

N1 - Funding Information: This work is based on research funded in part by the Bill & Melinda Gates Foundation (Investment ID OPP1093639); with UK aid from the UK Government (Project 202040) through GALVmed; and Wellcome through a Pathfinder Award (103127, KDR, IHG); a Wellcome Strategic Award to the Division of Biological Chemistry and Drug Discovery (100476, IHG); Wellcome awards for funding of the Mode of Action group (105021 and 218448, SW, IHG, DH).

PY - 2022/4/14

Y1 - 2022/4/14

N2 - African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites Trypanosoma congolense and Trypanosoma vivax, is a major problem in cattle and other livestocks in sub-Saharan Africa. Current treatments are threatened by the emergence of drug resistance and there is an urgent need for new, effective drugs. Here, we report the repositioning of a compound series initially developed for the treatment of human African trypanosomiasis. A medicinal chemistry program, focused on deriving more soluble analogues, led to development of a lead compound capable of curing cattle infected with both T. congolense and T. vivax via intravenous dosing. Further optimization has the potential to yield a single-dose intramuscular treatment for this disease. Comprehensive mode of action studies revealed that the molecular target of this promising compound and related analogues is the cyclin-dependent kinase CRK12.

AB - African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites Trypanosoma congolense and Trypanosoma vivax, is a major problem in cattle and other livestocks in sub-Saharan Africa. Current treatments are threatened by the emergence of drug resistance and there is an urgent need for new, effective drugs. Here, we report the repositioning of a compound series initially developed for the treatment of human African trypanosomiasis. A medicinal chemistry program, focused on deriving more soluble analogues, led to development of a lead compound capable of curing cattle infected with both T. congolense and T. vivax via intravenous dosing. Further optimization has the potential to yield a single-dose intramuscular treatment for this disease. Comprehensive mode of action studies revealed that the molecular target of this promising compound and related analogues is the cyclin-dependent kinase CRK12.

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U2 - 10.1021/acs.jmedchem.1c02104

DO - 10.1021/acs.jmedchem.1c02104

M3 - Article

C2 - 35303411

SN - 0022-2623

VL - 65

SP - 5606

EP - 5624

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 7

ER -

Repositioning of a diaminothiazole series confirmed to target the cyclin-dependent kinase CRK12 for use in the treatment of African animal trypanosomiasis

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

A Platform for Drug Target Deconvolution and Exploitation

Chemical Biology: Leveraging Phenotypic Hits Against Kinetoplastids (Strategic Grant)

New Treatment for African Animal Trypanosomiasis (Joint with GalvMed)

Cite this

Repositioning of a diaminothiazole series confirmed to target the cyclin-dependent kinase CRK12 for use in the treatment of African animal trypanosomiasis

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

A Platform for Drug Target Deconvolution and Exploitation

Chemical Biology: Leveraging Phenotypic Hits Against Kinetoplastids (Strategic Grant)

New Treatment for African Animal Trypanosomiasis (Joint with GalvMed)

Cite this