Optimizing small molecule inhibitors of calcium-dependent protein kinase 1 to prevent infection by toxoplasma gondii
Toxoplasma gondii is sensitive to bulky pyrazolo [3,4-d] pyrimidine (PP) inhibitors due to the presence of a Gly gatekeeper in the essential calcium dependent protein kinase 1 (CDPK1). Here we synthesized a number of new derivatives of 3-methyl-benzyl-PP (3-MB-PP, or 1). The potency of PP analogues in inhibiting CDPK1 enzyme activity in vitro (low nM IC50 values) and blocking parasite growth in host cell monolayers in vivo (low μM EC 50 values) were highly correlated and occurred in a CDPK1-specific manner. Chemical modification of the PP scaffold to increase half-life in the presence of microsomes in vitro led to identification of compounds with enhanced stability while retaining activity. Several of these more potent compounds were able to prevent lethal infection with T. gondii in the mouse model. Collectively, the strategies outlined here provide a route for development of more effective compounds for treatment of toxoplasmosis and perhaps related parasitic diseases.
Lourido, Sebastian,Zhang, Chao,Lopez, Michael S.,Tang, Keliang,Barks, Jennifer,Wang, Qiuling,Wildman, Scott A.,Shokat, Kevan M.,Sibley, L. David
p. 3068 - 3077
(2013/06/05)
MODULATION OF PROTEIN TRAFFICKING
Compounds and compositions are provided for treatment or amelioration of one or more disorders characterized by defects in protein trafficking. A method of treating a disorder characterized by impaired protein trafficking includes administering to a subject or contacting a cell with a compound of Formula I: [formula here] or pharmaceutically acceptable salts or derivatives thereof.
-
Page/Page column 54; 68
(2009/06/27)
Generation of monospecific nanomolar tyrosine kinase inhibitors via a chemical genetic approach
Selective protein kinase inhibitors are highly sought after as tools for studying cellular signal transduction cascades, yet few have been discovered due to the highly conserved fold of kinase catalytic domains. Through a combination of small molecule syn
Bishop, Anthony C.,Kung, Chi-Yun,Shah, Kavita,Witucki, Laurie,Shokat, Kevan M.,Liu, Yi
p. 627 - 631
(2007/10/03)
More Articles about upstream products of 221243-89-6