GDC-0134 (RG6000) is a modulator targeting dual leucine zipper kinase ( DLK ) that can cross the blood-brain barrier. By inhibiting the kinase activity of DLK, GDC-0134 blocks the activation of the downstream JNK signaling pathway, suppresses DLK-dependent retrograde signal transduction of axon-to-soma degeneration, and exerts neuroprotective activity. GDC-0134 reduces TDP-43 protein aggregation and decreases the degree of neuromuscular junction denervation in motor neurons. GDC-0134 can be used in the research of amyotrophic lateral sclerosis (ALS), Alzheimer's disease and other DLK-related neurodegenerative diseases [1].
In Vivo, GDC-0134 increases the level of neurofilament light chain protein (NFL) in the plasma of adult wild-type mice and induces phenotypes associated with sensory neuropathy[2]. GDC-0134 inhibits the activation of the JNK pathway downstream of DLK in the SOD1G93A mouse ALS model, and reduces the degree of denervation at neuromuscular junctions in mice[3].
In Vitro, GNE-3511, a structurally homologous DLK kinase inhibitor of GDC-0134, disrupts neurofilament 200 (NF200) and βIII-tubulin, leading to axonal cytoskeleton disorganization, in in vitro cultured dorsal root ganglion (DRG) neurons[2].
References:
[1]. Hoffmann-Emery F, et al. Development of a Practical and Greener Process for the Dual Leucine Zipper Kinase Inhibitor GDC-0134 Comprising Two SNAr Reactions, Oxidation and Suzuki Coupling[J]. Organic Process Research & Development, 2022, 26(2): 313-322.
[2]. Minaei A, et al. Novel neuroprotective strategy based on inhibition of acute axonal palmitoylation of dual leucine-zipper kinase[J]. Neural Regeneration Research, 10.4103.
[3]. Palomo V, et al. Protein kinase inhibitors for amyotrophic lateral sclerosis therapy[J]. British Journal of Pharmacology, 2021, 178(6): 1316-1335.
In Vivo, GDC-0134 increases the level of neurofilament light chain protein (NFL) in the plasma of adult wild-type mice and induces phenotypes associated with sensory neuropathy[2]. GDC-0134 inhibits the activation of the JNK pathway downstream of DLK in the SOD1G93A mouse ALS model, and reduces the degree of denervation at neuromuscular junctions in mice[3].
In Vitro, GNE-3511, a structurally homologous DLK kinase inhibitor of GDC-0134, disrupts neurofilament 200 (NF200) and βIII-tubulin, leading to axonal cytoskeleton disorganization, in in vitro cultured dorsal root ganglion (DRG) neurons[2].
References:
[1]. Hoffmann-Emery F, et al. Development of a Practical and Greener Process for the Dual Leucine Zipper Kinase Inhibitor GDC-0134 Comprising Two SNAr Reactions, Oxidation and Suzuki Coupling[J]. Organic Process Research & Development, 2022, 26(2): 313-322.
[2]. Minaei A, et al. Novel neuroprotective strategy based on inhibition of acute axonal palmitoylation of dual leucine-zipper kinase[J]. Neural Regeneration Research, 10.4103.
[3]. Palomo V, et al. Protein kinase inhibitors for amyotrophic lateral sclerosis therapy[J]. British Journal of Pharmacology, 2021, 178(6): 1316-1335.