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 Albrecht; Matt 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

doi:10.1038/s41586-018-0356-z

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

Research output: Contribution to journal › Article

36 Citations (Scopus)

502 Downloads (Pure)

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 language	English
Pages (from-to)	192-197
Number of pages	6
Journal	Nature
Volume	560
Issue number	7717
Early online date	25 Jul 2018
DOIs	https://doi.org/10.1038/s41586-018-0356-z
Publication status	Published - 9 Aug 2018

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10.1038/s41586-018-0356-z

Author Accepted ManuscriptAccepted author manuscript, 17.3 MB
Author Accepted Manuscript: Supporting InformationAccepted author manuscript, 15.3 MB
Author Accepted Manuscript: Extended Data Tables 1-6Accepted author manuscript, 280 KB
Author Accepted Manuscript: Figures 1-5Accepted author manuscript, 9.19 MB
Author Accepted Manuscript: Extended Data Figures 1-2Accepted author manuscript, 300 KB

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Projects

1 Finished
2 Active

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

Fairlamb, A., Field, M., Gilbert, I., Gray, D., Horn, D. & Wyatt, P.

Wellcome Trust

1/01/15 → 31/12/20

Project: Research

Protein Glycosylation in Trypanosomes: Defining and Exploiting a Biological System (Senior Investigator Award)

Ferguson, M.

Wellcome Trust

1/10/13 → 30/06/22

Project: Research

A Translational Engine for Biomedical Discoveries (Strategic Grant)

Fairlamb, A. & Gilbert, I.

Wellcome Trust

1/01/13 → 30/09/15

Project: Research

Profiles

Fairlamb, Alan

Biological Chemistry and Drug Discovery - Consulting Professor & Consulting Professor of Biochemistry

Person: Academic

Cite this

Wyllie, S., Thomas, M., Patterson, S., Crouch, S., De Rycker, M., Lowe, R., Gresham, S., Urbaniak, M. D., Otto, T. D., Stojanovski, L., Simeons, F. R. C., Manthri, S., MacLean, L. M., Zuccotto, F., Homeyer, N., Pflaumer, H., Boesche, M., Sastry, L., Connolly, P., ... Gilbert, I. H. (2018). Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis. Nature, 560(7717), 192-197. https://doi.org/10.1038/s41586-018-0356-z

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.",

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

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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 journal › Article

TY - JOUR

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AU - Thomas, Michael

AU - Patterson, Stephen

AU - Crouch, Sabrinia

AU - De Rycker, Manu

AU - Lowe, Rhiannon

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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AB - 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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DO - 10.1038/s41586-018-0356-z

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