4TZR

Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1561

4TZR の概要

• エントリーDOI: 10.2210/pdb4tzr/pdb
• 分子名称: Calmodulin-domain protein kinase 1, 1-{4-amino-3-[2-(cyclopropyloxy)quinolin-6-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-2-methylpropan-2-ol (3 entities in total)
• 機能のキーワード: serine/threonine protein kinase, transferase, calcium-binding, atp-binding, bumped kinase inhibitor
• 由来する生物種: Toxoplasma gondii
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55617.35

構造登録者

Merritt, E.A. (登録日: 2014-07-10, 公開日: 2014-08-27, 最終更新日: 2023-12-27)

主引用文献

Vidadala, R.S.,Rivas, K.L.,Ojo, K.K.,Hulverson, M.A.,Zambriski, J.A.,Bruzual, I.,Schultz, T.L.,Huang, W.,Zhang, Z.,Scheele, S.,DeRocher, A.E.,Choi, R.,Barrett, L.K.,Siddaramaiah, L.K.,Hol, W.G.,Fan, E.,Merritt, E.A.,Parsons, M.,Freiberg, G.,Marsh, K.,Kempf, D.J.,Carruthers, V.B.,Isoherranen, N.,Doggett, J.S.,Van Voorhis, W.C.,Maly, D.J.
Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis.
J. Med. Chem., 59:6531-6546, 2016

PubMed Abstract: New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy.

PubMed: 27309760
DOI: 10.1021/acs.jmedchem.6b00760

実験手法

X-RAY DIFFRACTION (2 Å)