AGC kinase homology requires and enables co-targeting for CNS regeneration
Axon regrowth in the central nervous system (CNS) is constrained by robust regulatory networks. 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…
In the central nervous system (CNS), axon regrowth is limited by complex regulatory networks. This study demonstrates that optimal neurite outgrowth in rodent and human CNS neurons can be achieved by simultaneously inhibiting kinases from four closely related clades within the protein kinase A, G, and C (AGC) family. These kinases have ancestral roots in cytoskeletal dynamics, resource allocation, and polarized cell growth, and share a common domain architecture, allowing for polypharmacology or co-engagement by a single small molecule.
Through phenotype-guided optimization of an existing tool compound that has demonstrated efficacy in mouse spinal cord injury models, researchers developed TMP-316, a drug candidate that selectively targets these AGC kinases while avoiding broader kinome engagement. A single intrathecal dose of TMP-316 resulted in sustained motor recovery in a rat cervical hemisection model.
This research reveals that polypharmacology is both required and enabled by the shared evolutionary origins of these kinases, providing a novel therapeutic discovery principle for conditions governed by functionally overlapping targets.
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