| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T07102 | ||||
| Target Name | Rho-associated protein kinase 1 | ||||
| Target Type | Clinical Trial |
||||
| Drug Potency against Target | H-1152 | Drug Info | IC50 = 6 nM | ||
| SB-747651A | Drug Info | IC50 = 38 nM | [529701] | ||
| Action against Disease Model | Cethrin | Local inhibition of Rho signaling by cell-permeable recombinant protein BA-210 prevents secondary damage and promotes functional recovery following acute spinal cord injury. Treatment with BA-210 in rats with thoracic spinal cord contusion increased tissue sparing around the lesion area and led to significant improvement of locomotor function. In mice, BA-210 improved functional outcome when treatment was either applied at the time of injury or delayed by 24 h. In both rats and mice, treatment with BA-210 was well tolerated. Rats gained body weight normally, and BA-210 treatment had no impact on the development of allodynia. Inactivating Rho with BA-210 holds promise for treating patients with SCI. | [552894] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | We studied Rho-associated kinase(ROCKII) mutant mice to probe this pathway genetically. ROCKII(-/-) dorsal root ganglion neurons are less sensitive to inhibition by Nogo proteinor by chondroitin sulfate proteoglycan in vitro. We examined adult ROCKII(-/-) mice in two injury paradigms, cervical multilevel dorsal rhizotomy and midthoracic dorsal spinal cord hemisection. Afterdorsal root crush injury, the ROCKII(-/-) mice recovered use of the affected forepaw more quickly than did controls. Moreover, multiple classes of sensory axons regenerated across the dorsal root entry zone into the spinal cord of mice lacking ROCKII. After the spinal cord injury, ROCKII(-/-) mice showed enhanced local growth of raphespinal axons in the caudal spinal cord and corticospinal axons into the lesion site. Improved functional recovery was not observed by Basso Mouse Scale score following dorsal hemisection, likely due to developmental defects in the nervous system. Together, these findings demonstrate that the ROCKII gene product limits axonal growth after CNS tra uMa | ||||
| References | |||||
| Ref 529701 | J Med Chem. 2008 Sep 25;51(18):5663-79.Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase. | ||||
| Ref 552894 | Local inhibition of Rho signaling by cell-permeable recombinant protein BA-210 prevents secondary damage and promotes functional recovery following acute spinal cord injury. J Neurotrauma. 2008 Nov;25(11):1309-22. doi: 10.1089/neu.2008.0613. | ||||
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