Spinal cord injury is a devastating condition with lifelong consequences that may include paralysis, chronic pain, and autonomic dysreflexia. Central nervous system (CNS) axons typically fail to regenerate after injury. This leads to irreversible losses of neuronal connectivity and associated functions. At present, there are no approved pharmacological treatments to promote regeneration and repair of CNS axons. These processes are thwarted by two separate mechanisms: 1) a lack of intrinsic regenerative capacity in adult CNS neurons, and 2) the inhibitory microenvironment confronting damaged axons. We developed and validated a promising therapeutic strategy that involves co-targeting Ribosomal S6 Kinase (a mediator of intrinsic inhibition) and Rho kinase (a mediator of extrinsic inhibition). We identified a single small molecule that co-engages both targets and strongly promotes axon growth from CNS neurons in vitro and in vivo. We performed medicinal chemistry, structure-activity-relationship (SAR), pharmacokinetic, and toxicity studies and generated a lead compound suitable for preclinical development. Our current goal is to move this promising compound towards a Phase 1 clinical trial.