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

## TL;DR

Scientists developed a selective TAOK1 inhibitor and a pan-TAOK activator to study their roles in diseases like breast cancer and neurodegeneration.

## Contribution

The discovery of the first TAOK1-selective inhibitor and an unexpected pan-TAOK activator through medicinal chemistry.

## Key findings

- VU6083859 is a selective TAOK1 inhibitor with high selectivity over TAOK2 and TAOK3.
- VU6080195 is a pan-TAOK activator with activity across all three TAOK isoforms.
- Both compounds show CNS penetration and modest pharmacokinetics in rats.

## Abstract

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 IC50 = 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 EC50 = 270 nM, TAOK2
EC50 = 1,376 nM, TAOK3 EC50 = 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
ps > 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.