9Z5L

Crystal structure of TgCDPK1 with bound inhibitor

This is a non-PDB format compatible entry.

Summary for 9Z5L

• Entry DOI: 10.2210/pdb9z5l/pdb
• Descriptor: Non-specific serine/threonine protein kinase, 1-[(1s,4s)-4-(methylamino)cyclohexyl]-3-{[4-(trifluoromethyl)pyridin-2-yl]oxy}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3 entities in total)
• Functional Keywords: calcium-dependent protein kinase, ef hand, kinase domain, cell invasion, cell invasion-inhibitor complex, cell invasion/inhibitor
• Biological source: Toxoplasma gondii
• Total number of polymer chains: 1
• Total formula weight: 59809.61

Authors

Dhillon, A.,Sibley, L.D.,Nelson, C.,Fremont, D.,Janetka, J.W. (deposition date: 2025-11-12, release date: 2026-08-05)

Primary citation

Mannino, M.P.,Gokanapalle, A.,Patil, S.,Kooner, A.S.,Meena, C.L.,Medcalf, M.,Vilza, I.,Barks, J.,Fu, Y.,Xia, J.,Nix, J.C.,Nelson, C.,Fremont, D.,Dhillon, A.,Sibley, L.D.,Janetka, J.W.
Lead Optimization of TgCDPK1 Inhibitors for the Treatment of Toxoplasmosis.
J.Med.Chem., 69:14365-14389, 2026

PubMed Abstract: is an important opportunistic pathogen that infects many individuals and threatens the health of those with compromised immunity. Current therapies are unable to eradicate chronic infections and pose risks of adverse reactions. Using X-ray structure-based drug design, we have developed a new series of biaryl-substituted pyrazolopyrimidine inhibitors of the essential parasite enzyme calcium-dependent protein kinase 1 (TgCDPK1). These inhibitors have excellent potency against the enzyme and antiparasitic activity. We further optimized the compounds for increased metabolic stability, lowered plasma protein binding, decreased efflux, and improved pharmacokinetics (PK). Several of the inhibitors had desirable PK with high oral bioavailability, low clearance, and extended half-life, leading to excellent compound exposure in the plasma and brain over a 24-h period. Three compounds were tested during acute infection in both immunocompetent and immunocompromised mice. We identified as a promising preclinical candidate to treat toxoplasmosis.

PubMed: 42231809
DOI: 10.1021/acs.jmedchem.6c00065

Experimental method

X-RAY DIFFRACTION (1.8 Å)