Updated project metadata. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive paralysis resulting from specific degeneration of upper and lower motor neurons (MNs). Chronic neuroinflammation, mediated by activated microglia, is a hallmark of patients diagnosed with ALS, and correlates with disease pathogenesis. Protecting MNs, particularly from toxic insults caused by neuroinflammation, could lead to effective treatments of ALS patient. Here, we report a screening campaign identifying a series of pyrazolotriazines that cell-autonomously protect MNs against neuroinflammation. We demonstrate that these compounds inhibit Cyclin-dependent kinase 5 (CDK5) and Glycogen synthase kinase 3 (GSK3), and we use phospho-proteomics to show that neuroprotection is linked to alterations in microtubule dynamics.