Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis

Susan Wyllie, Michael Thomas, Stephen Patterson, Sabrinia Crouch, Manu De Rycker, Rhiannon Lowe, Stephanie Gresham, Michael D. Urbaniak, Thomas D. Otto, Laste Stojanovski, Frederick R. C. Simeons, Sujatha Manthri, Lorna M. MacLean, Fabio Zuccotto, Nadine Homeyer, Hannah Pflaumer, Markus Boesche, Lalitha Sastry, Paul Connolly, Sebastian AlbrechtMatt Berriman, Gerard Drewes, David W. Gray, Sonja Ghidelli-Disse, Susan Dixon, Jose M. Fiandor, Paul G. Wyatt, Michael A. J. Ferguson, Alan H. Fairlamb, Timothy J. Miles, Kevin D. Read, Ian H. Gilbert

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Abstract

Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis.

Original languageEnglish
Pages (from-to)192-197
Number of pages6
JournalNature
Volume560
Issue number7717
Early online date25 Jul 2018
DOIs
Publication statusPublished - 9 Aug 2018

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Visceral Leishmaniasis
Cyclin-Dependent Kinases
Pharmaceutical Preparations
Toxicology
Parasites
Phosphotransferases
Pharmacokinetics
Morbidity
Mortality

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Wyllie, Susan ; Thomas, Michael ; Patterson, Stephen ; Crouch, Sabrinia ; De Rycker, Manu ; Lowe, Rhiannon ; Gresham, Stephanie ; Urbaniak, Michael D. ; Otto, Thomas D. ; Stojanovski, Laste ; Simeons, Frederick R. C. ; Manthri, Sujatha ; MacLean, Lorna M. ; Zuccotto, Fabio ; Homeyer, Nadine ; Pflaumer, Hannah ; Boesche, Markus ; Sastry, Lalitha ; Connolly, Paul ; Albrecht, Sebastian ; Berriman, Matt ; Drewes, Gerard ; Gray, David W. ; Ghidelli-Disse, Sonja ; Dixon, Susan ; Fiandor, Jose M. ; Wyatt, Paul G. ; Ferguson, Michael A. J. ; Fairlamb, Alan H. ; Miles, Timothy J. ; Read, Kevin D. ; Gilbert, Ian H. / Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis. In: Nature. 2018 ; Vol. 560, No. 7717. pp. 192-197.
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abstract = "Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis.",
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Wyllie, S, Thomas, M, Patterson, S, Crouch, S, De Rycker, M, Lowe, R, Gresham, S, Urbaniak, MD, Otto, TD, Stojanovski, L, Simeons, FRC, Manthri, S, MacLean, LM, Zuccotto, F, Homeyer, N, Pflaumer, H, Boesche, M, Sastry, L, Connolly, P, Albrecht, S, Berriman, M, Drewes, G, Gray, DW, Ghidelli-Disse, S, Dixon, S, Fiandor, JM, Wyatt, PG, Ferguson, MAJ, Fairlamb, AH, Miles, TJ, Read, KD & Gilbert, IH 2018, 'Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis', Nature, vol. 560, no. 7717, pp. 192-197. https://doi.org/10.1038/s41586-018-0356-z

Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis. / Wyllie, Susan; Thomas, Michael; Patterson, Stephen; Crouch, Sabrinia; De Rycker, Manu; Lowe, Rhiannon; Gresham, Stephanie; Urbaniak, Michael D.; Otto, Thomas D.; Stojanovski, Laste; Simeons, Frederick R. C.; Manthri, Sujatha; MacLean, Lorna M.; Zuccotto, Fabio; Homeyer, Nadine; Pflaumer, Hannah; Boesche, Markus; Sastry, Lalitha; Connolly, Paul; Albrecht, Sebastian; Berriman, Matt; Drewes, Gerard; Gray, David W.; Ghidelli-Disse, Sonja; Dixon, Susan; Fiandor, Jose M.; Wyatt, Paul G.; Ferguson, Michael A. J.; Fairlamb, Alan H.; Miles, Timothy J. (Lead / Corresponding author); Read, Kevin D. (Lead / Corresponding author); Gilbert, Ian H. (Lead / Corresponding author).

In: Nature, Vol. 560, No. 7717, 09.08.2018, p. 192-197.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Wyllie, Susan

AU - Thomas, Michael

AU - Patterson, Stephen

AU - Crouch, Sabrinia

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AU - Gresham, Stephanie

AU - Urbaniak, Michael D.

AU - Otto, Thomas D.

AU - Stojanovski, Laste

AU - Simeons, Frederick R. C.

AU - Manthri, Sujatha

AU - MacLean, Lorna M.

AU - Zuccotto, Fabio

AU - Homeyer, Nadine

AU - Pflaumer, Hannah

AU - Boesche, Markus

AU - Sastry, Lalitha

AU - Connolly, Paul

AU - Albrecht, Sebastian

AU - Berriman, Matt

AU - Drewes, Gerard

AU - Gray, David W.

AU - Ghidelli-Disse, Sonja

AU - Dixon, Susan

AU - Fiandor, Jose M.

AU - Wyatt, Paul G.

AU - Ferguson, Michael A. J.

AU - Fairlamb, Alan H.

AU - Miles, Timothy J.

AU - Read, Kevin D.

AU - Gilbert, Ian H.

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DO - 10.1038/s41586-018-0356-z

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