TY - JOUR
T1 - KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission
AU - Kuhen, Kelli L.
AU - Chatterjee, Arnab K.
AU - Rottmann, Matthias
AU - Gagaring, Kerstin
AU - Borboa, Rachel
AU - Buenviaje, Jennifer
AU - Chen, Zhong
AU - Francek, Carolyn
AU - Wu, Tao
AU - Nagle, Advait
AU - Barnes, S. Whitney
AU - Plouffe, David
AU - Lee, Marcus C.S.
AU - Fidock, David A.
AU - Graumans, Wouter
AU - Van De Vegte-Bolmer, Marga
AU - Van Gemert, Geert J.
AU - Wirjanata, Grennady
AU - Sebayang, Boni
AU - Marfurt, Jutta
AU - Russell, Bruce
AU - Suwanarusk, Rossarin
AU - Price, Ric N.
AU - Nosten, Francois
AU - Tungtaeng, Anchalee
AU - Gettayacamin, Montip
AU - Sattabongkot, Jetsumon
AU - Taylor, Jennifer
AU - Walker, John R.
AU - Tully, David
AU - Patra, Kailash P.
AU - Flannery, Erika L.
AU - Vinetz, Joseph M.
AU - Renia, Laurent
AU - Sauerwein, Robert W.
AU - Winzeler, Elizabeth A.
AU - Glynne, Richard J.
AU - Diagana, Thierry T.
PY - 2014/9
Y1 - 2014/9
N2 - Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.
AB - Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.
UR - http://www.scopus.com/inward/record.url?scp=84906079854&partnerID=8YFLogxK
U2 - 10.1128/AAC.02727-13
DO - 10.1128/AAC.02727-13
M3 - Article
C2 - 24913172
AN - SCOPUS:84906079854
SN - 0066-4804
VL - 58
SP - 5060
EP - 5067
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 9
ER -
