Neuroprotectant development from small molecule inhibitors of CHOP/ATF4 expression

Glaucoma is a neurodegenerative disease that is in urgent need of neuroprotective therapies. We previously revealed the critical role of neuronal endoplasmic reticulum (ER) stress induced by optic nerve injury in glaucomatous neurodegeneration. We also demonstrated that modulation of the ATF4-CHOP branch of ER stress provides significant neuroprotection. Here, we present multiple new chemical series identified by high-throughput screening that inhibit ER stress-induced C/EBP homologous protein (CHOP) expression. We perform a structure-activity relationship analysis of one "hit" compound and establish two analogs with potent activities on inhibiting the expression of CHOP and activating transcription factor 4 (ATF4). We further demonstrate their neuroprotective efficacy in two optic neuropathy models; in both models, they increase survival of retinal ganglion cell somata and axons and preserve visual function. Together, this proof-of-concept evidence establishes the new ER stress modulators as promising candidates for further drug development to provide neuroprotective therapy for glaucoma and other optic neuropathies, and potentially for diverse CNS axonopathies.