TC-G-1008

TC-G 1008 is a recommended GPR39 tool compound with a favorable profile, confirmed independently by multiple research groups. S. Peukert et al (Med. Chem. Lett. 2014, 5, 1114−1118) is providing initial profiling data on a limited set of ~ 30 kinases under standard conditions, some structurally related targets like ghrelin and the neurotensin-1 receptor and a broad set of representative off-targets without any molecular evidence for relevant off-target activity. However, the closely related compound 22 described in the initial paper already demonstrated an unexpected pharmacology and the authors speculate about the involvement of potential unidentified off-targets. Y. Shimizu et al (Biochem Pharmacol 2017 Sep 15;140:105-114) demonstrated that TC-G 1008 (aka GPR39-C3) induced the internalization of GFP-tagged GPR39 suggesting a more complex MoA that a simple allosteric Zn2+ cooperative agonism. In addition, S. Sato et al (Mol Pharmacol 2016, 90:726–737) speculated that the affinity of TC-G-1008 to other targets might be modulated in the presence of Zn2+ ions as well, highlighting 5HT1A, a(1A)-adrenoreceptor, b2-adrenergic receptor, GPR68, and GPRC6A as Zn2+ dependent proteins. The final evidence that TC-G-1008 is not as selective as initially proposed, is provided by U. Doboszewska et al (Cellular and Molecular Life Sciences (2023) 80:133) describing CREB activation in a GPR39 knockout in vivo experiment at a low dose of 10 mg/kg p.o. (resulting in a total plasma Cmax of 1.4 µM - (FUB 0,9%)). This isolated observation suggests that an off-target is already modulated in the activity range of 10-20 nM. Cellular characterization of TC-G-1008 in GPR39 -/- knockouts should be recommended to further evaluate the activity range of pharmacological contributions by off-targets. Despite these limited reports of off-target activity, TC-G 1008 is the best available probe for GPR39. Other published GPR39 ligands like AZ1395, AZ4237, AZ7914,CMAP 7, GSK2636771, LY2784544 or TM-N1324 are less characterized.