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 | |
| Publication status | Published - 9 Aug 2018 |
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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
T1 - Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis
AU - Wyllie, Susan
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.
PY - 2018/8/9
Y1 - 2018/8/9
N2 - 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.
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.
U2 - 10.1038/s41586-018-0356-z
DO - 10.1038/s41586-018-0356-z
M3 - Article
C2 - 30046105
AN - SCOPUS:85051268254
VL - 560
SP - 192
EP - 197
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7717
ER -