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Here we show that optimal neurite outgrowth in rodent and human CNS neurons is achieved by co-inhibition of kinases across four closely related clades within the protein kinase A, G, and C (AGC) family. The kinases derive from ancestral regulators of cytoskeletal dynamics, resource allocation, and polarized cell growth. Their shared domain architecture makes polypharmacology (co-engagement by a single small molecule) feasible. Phenotype-guided optimization of a tool compound with established efficacy in mouse spinal cord injury models yielded TMP-316, a drug candidate engaging these AGC kinases with selectivity against the broader kinome. A single intrathecal dose of TMP-316 produced sustained motor recovery in a rat cervical hemicontusion model. 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