8CJO

Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-06-004

Summary for 8CJO

• Entry DOI: 10.2210/pdb8cjo/pdb
• Descriptor: Tryptophan 5-hydroxylase 1, FE (III) ION, 1-[(3~{S})-3-(4-chloranyl-2-fluoranyl-phenyl)-1,4,8-triazatricyclo[7.4.0.0^{2,7}]trideca-2(7),8-dien-4-yl]-2-(2-ethyl-6-methyl-pyridin-3-yl)oxy-ethanone, ... (4 entities in total)
• Functional Keywords: catalytic domain of human tryptophan hydroxylase 1 (tph1), inhibitor complex, metal binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 37963.43

Authors

Schuetz, A.,Mallow, K.,Nazare, M.,Specker, E.,Heinemann, U. (deposition date: 2023-02-13, release date: 2024-01-10)

Primary citation

Specker, E.,Wesolowski, R.,Schutz, A.,Matthes, S.,Mallow, K.,Wasinska-Kalwa, M.,Winkler, L.,Oder, A.,Alenina, N.,Pleimes, D.,von Kries, J.P.,Heinemann, U.,Bader, M.,Nazare, M.
Structure-Based Design of Xanthine-Imidazopyridines and -Imidazothiazoles as Highly Potent and In Vivo Efficacious Tryptophan Hydroxylase Inhibitors.
J.Med.Chem., 66:14866-14896, 2023

PubMed Abstract: Tryptophan hydroxylases catalyze the first and rate-limiting step in the biosynthesis of serotonin, a well-known neurotransmitter that plays an important role in multiple physiological functions. A reduction of serotonin levels, especially in the brain, can cause dysregulation leading to depression or insomnia. In contrast, overproduction of peripheral serotonin is associated with symptoms like carcinoid syndrome and pulmonary arterial hypertension. Recently, we developed a class of TPH inhibitors based on xanthine-benzimidazoles, characterized by a tripartite-binding mode spanning the binding sites of the cosubstrate pterin and the substrate tryptophan and by chelation of the catalytic iron ion. Herein, we describe the structure-based development of a second generation of xanthine-imidiazopyridines and -imidazothiazoles designed to inhibit TPH1 in the periphery while preventing the interaction with TPH2 in the brain. Lead compound (TPT-004) shows superior pharmacokinetic and pharmacodynamic properties as well as efficacy in preclinical models of peripheral serotonin attenuation and colorectal tumor growth.

PubMed: 37905925
DOI: 10.1021/acs.jmedchem.3c01454

Experimental method

X-RAY DIFFRACTION (1.86633703305 Å)