The serotonin transporter (SERT), a member of the neurotransmitter sodium symporter (NSS) family, is responsible for the reuptake of serotonin from the synaptic cleft to maintain neurotransmitter homeostasis. SERT is established as an important target in the treatment of anxiety and depression. Because a high-resolution crystal structure is not available, a computational model of SERT was built based upon the x-ray coordinates of the leucine transporter LeuT, a bacterial NSS homolog. The model was used to develop the first SERT structure-based pharmacophore. Virtual screening (VS) of a small molecule structural library using the generated SERT computational model yielded candidate ligands of diverse scaffolds. Pharmacological analysis of the VS hits identified two SERT-selective compounds, potential lead compounds for further SERT-related medication development.
Aim
To further characterize the selectivity, mechanism-of-action and
therapeutic efficacy of the novel small molecule inhibitor, SKI-178.
Methods
Using the state-of-the-art Cellular Thermal Shift Assay (CETSA)
technique to detect “direct target engagement” of proteins
intact cells, in vitro and in vivo assays,
pharmacological assays and multiple mouse models of acute myeloid leukemia
(AML).
Results
Herein, we demonstrate that SKI-178 directly target engages both
Sphingosine Kinase 1 and 2. We also present evidence that, in addition to
its actions as a Sphingosine Kinase Inhibitor, SKI-178 functions as a
microtubule network disrupting agent both in vitro and in
intact cells. Interestingly, we separately demonstrate that simultaneous
SphK inhibition and microtubule disruption synergistically induces apoptosis
in AML cell lines. Furthermore, we demonstrate that SKI-178 is well
tolerated in normal healthy mice. Most importantly, we demonstrate that
SKI-178 has therapeutic efficacy in several mouse models of AML.
Conclusion
SKI-178 is a multi-targeted agent that functions both as an inhibitor
of the SphKs as well as a disruptor of the microtubule network. SKI-178
induced apoptosis arises from a synergistic interaction of these two
activities. SKI-178 is safe and effective in mouse models of AML, supporting
its further development as a multi-targeted anti-cancer therapeutic
agent.
The authors suggest that given the long-awaited availability of credible three-dimensional structures for the SERT and related monoamine transporter proteins, cutting-edge computational methods should be the linchpin of future drug discovery efforts regarding monoamine-based antidepressant lead compounds. Because these transporter inhibitors cause a ubiquitous increase in extraneuronal neurotransmitter levels leading to side and adverse therapeutic effects, the drug discovery should extend to appropriate manipulation of the 'downstream' receptors affected by the neurotransmitter boost. Efficient use of new computational strategies will accelerate the drug discovery process and reduce its economic burden.
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