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Discovery of VU6083859, a TAOK1 Selective Inhibitor, and VU6080195, a pan-TAOK Activator
Daniel C Schultz1, Lauren C Parr2, Hunter Sweet1
1Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
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 (Kps > 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.
Insights
Researchers developed novel TAO kinase modulators, including the first TAOK1-selective inhibitor and a pan-TAOK activator. These compounds show potential for studying neurodevelopmental disorders and tauopathies.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Biochemistry
Background:
- Thousand and one (TAO) kinases (TAOK1, TAOK2, TAOK3) are implicated in breast cancer, tauopathies, and neurodevelopmental disorders (NDDs).
- Existing pan-TAO kinase inhibitors, like compound 43, have limitations including poor pharmacokinetics (PK) and off-target effects.
- Development of isoenzyme-selective TAO kinase modulators is crucial for understanding their specific roles in NDDs and tau pathology.
Purpose of the Study:
- To expand the chemical space around compound 43 through medicinal chemistry.
- To discover novel, isoenzyme-selective TAO kinase inhibitors and activators.
- To develop chemical probes for validating TAO kinase modulation in the central nervous system (CNS).
Main Methods:
- Iterative medicinal chemistry optimization of a known TAO kinase inhibitor scaffold.
- Synthesis and characterization of novel chemical entities targeting TAO kinases.
- In vitro kinase assays to determine selectivity and potency (IC50, EC50) against TAOK1, TAOK2, and TAOK3.
- Assessment of kinase selectivity against a broad panel (Cerep 360).
- Evaluation of pharmacokinetic properties and CNS penetration in rat models.
Main Results:
- Discovery of VU6083859, the first TAOK1-selective inhibitor (TAOK1 IC50 = 158 nM; TAOK2/TAOK1 = 22; TAOK3/TAOK1 > 63).
- Identification of VU6080195, a pan-TAOK activator (TAOK1 EC50 = 270 nM, TAOK2 EC50 = 1,376 nM, TAOK3 EC50 = 503 nM), with a des-methyl congener acting as a TAOK1-preferring inhibitor.
- Both compounds exhibited modest rat PK and demonstrated CNS penetration (Kp > 0.15).
Conclusions:
- The developed TAO kinase ligands, VU6083859 and VU6080195, represent valuable chemical tools.
- These compounds provide a foundation for further optimization to probe TAO kinase roles in CNS disorders.
- The findings support the potential of TAO kinase modulation as a therapeutic strategy for NDDs and tauopathies.
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