Developing Dual Leucine Zipper Kinase Inhibitors for Glaucoma

Project Summary

Nerve cells called retinal ganglion cells form the connection between the eye and the brain. In glaucoma, these nerve cells die and vision is permanently lost. The only treatment for glaucoma has been to lower eye pressure. However, this can be difficult to achieve in some patients, while in others, the disease may progress despite pressure-lowering. A complementary approach is called neuroprotection, whereby drugs directly target the cell death pathways in retinal ganglion cells and make them more resistant to injury. Unfortunately, no neuroprotective agent has yet made it to the clinic.

In order to develop such a neuroprotective strategy, we previously screened genes to find those that would be the best drug targets. We showed that a protein called dual leucine zipper kinase (DLK) is critical for the death of retinal ganglion cells. Moreover, we identified two drugs originally created as anti-cancer agents, tozasertib and foretinib, that are reasonably effective inhibitors of DLK. Indeed, when these inhibitors were given to rats with glaucoma, there was a significant reduction in the amount of retinal ganglion cell death. While promising, both compounds, at their therapeutic doses, inhibit numerous other unrelated targets, leading to toxicity and undesired side effects.

We are currently working with medicinal chemists to modify the structures of tozasertib and foretinib in such a way that we improve their ability to target DLK and reduce their ability to target other gene products. If successful, this work will lead to the generation of compounds with improved selectivity for DLK. Since we and others have already used genetic approaches to show that DLK is an excellent neuroprotective target (i.e., the ""protected"" cells remain alive for extended periods of time and appear to be functional), these compounds could become the prototype for glaucoma neuroprotectives.