Discovery of VU6083859, a TAOK1 Selective Inhibitor, and VU6080195, a pan -TAOK Activator

High Resolution Image Download MS PowerPoint Slide The thousand and one (TAO) kinases, TAOK1, TAOK2, and TAOK3, have garnered great interest for their role in, and therapeutic potential for, breast cancer, neurodegeneration in human tauopathies, and a large number of neurodevelopmental disorders (NDDs). However, only one pan -TAO kinase inhibitor, referred to as compound 43, has been employed to pharmacologically validate this important family of kinases despite a poor pharmacokinetic(PK) profile and off-target liabilities. In order to understand the isoenzyme-specific role of TAOKs in NDDs and in regulating tau pathology, isoenzyme-selective inhibitors and activators are required. Here, we report on an iterative medicinal chemistry exercise to expand the chemical space around compound 43, which resulted in the first TAOK1 selective inhibitor VU6083859 (TAOK1 IC 50 = 158 nM; TAOK2/TAOK1 = 22; TAOK3/TAOK1 > 63; selective versus the Cerep 360 kinase panel) and quite unexpectedly, by virtue of a ‘magic methyl,’ a pan -TAOK activator, VU6080195 (TAOK1 EC 50 = 270 nM, TAOK2 EC 50 = 1,376 nM, TAOK3 EC 50 = 503 nM; note: the des -methyl congener is a TAOK1-preferring inhibitor). Both new kinase ligands showed modest rat PK, central nervous system (CNS) penetration ( K p s > 0.15) and therefore provide a foundation to further optimize this chemotype to probe and validate the role(s) of TAO kinase modulation in the CNS.