AGC kinase homology requires and enables co-targeting for CNS regeneration
Al-Ali, H.; Badillo-Martinez, A.; Awada, B.; Silver, B. B.; Elwardaney, O.; Buckle, R.; Johnson, G.; Sun, S.; Lendof, R.; Guhan, N.; Singh, P.; Lee, J.; Bixby, J.; Lemmon, V. · neuroscience · 2026-09-04 · 原文
DOI：10.64898/2026.08.28.746753作者：14 位
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 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. These findings reveal conditions under which polypharmacology is simultaneously required and enabled by shared evolutionary origins, illuminating a therapeutic discovery principle for pathologies governed by functionally overlapping targets.
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1. 人话版
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.
2. 领域脉络
本文类目：neuroscience，属于其所在研究脉络的最新进展。
3. 机制拆解
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.
4. 证据与数字
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.
5. 反例与边界
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