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Development of technology platforms to perform compound screens of human induced pluripotent stem cell (hiPSC)-derived neurons with relatively high throughput is essential to realize their potential for drug discovery. Here, we demonstrate the feasibility of high-throughput screening of hiPSC-derived neurons using a high-content, image-based approach focused on neurite growth, a process that is fundamental to formation of neural networks and nerve regeneration. From a collection of 4421 bioactive small molecules, we identified 108 hit compounds, including 37 approved drugs, that target molecules or pathways known to regulate neurite growth, as well as those not previously associated with this process. These data provide evidence that many pathways and targets known to play roles in neurite growth have similar activities in hiPSC-derived neurons that can be identified in an unbiased phenotypic screen. The data also suggest that hiPSC-derived neurons provide a useful system to study the mechanisms of action and off-target activities of the approved drugs identified as hits, leading to a better understanding of their clinical efficacy and toxicity, especially in the context of specific human genetic backgrounds. Finally, the hit set we report constitutes a sublibrary of approved drugs and tool compounds that modulate neurites. This sublibrary will be invaluable for phenotypic analyses and interrogation of hiPSC-based disease models as probes for defining phenotypic differences and cellular vulnerabilities in patient versus control cells, as well as for investigations of the molecular mechanisms underlying human neurite growth in development and maintenance of neuronal networks, and nerve regeneration.

High-throughput screen for compounds that modulate neurite growth of human induced pluripotent stem cell derived neurons