AGC kinase homology requires and enables co-targeting for CNS regeneration
- 1University of Miami Miller School of Medicine
Abstract
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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BibTeX
@misc{alali2026kinase,
title = {{AGC kinase homology requires and enables co-targeting for CNS regeneration}},
author = {H. Al-Ali and A. Badillo-Martinez and B. Awada and B. B. Silver and O. Elwardaney and R. Buckle and G. Johnson and S. Sun and R. Lendof and N. Guhan and P. Singh and J. Lee and J. Bixby and V. Lemmon},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.28.746753},
url = {https://www.biorxiv.org/content/10.64898/2026.08.28.746753v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - AGC kinase homology requires and enables co-targeting for CNS regeneration
AU - H. Al-Ali
AU - A. Badillo-Martinez
AU - B. Awada
AU - B. B. Silver
AU - O. Elwardaney
AU - R. Buckle
AU - G. Johnson
AU - S. Sun
AU - R. Lendof
AU - N. Guhan
AU - P. Singh
AU - J. Lee
AU - J. Bixby
AU - V. Lemmon
PY - 2026
DA - 2026/08/28
PB - bioRxiv
DO - 10.64898/2026.08.28.746753
UR - https://www.biorxiv.org/content/10.64898/2026.08.28.746753v1
AB - 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.
ER -