In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury
Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkin...
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| creator | Lagiakos, H Rachel Zou, Yefen Igawa, Hideyuki Therrien, Eric Lawrenz, Morgan Kato, Mitsunori Svensson, Mats Gray, Felicia Jensen, Kristian Dahlgren, Markus K Pelletier, Robert D Dingley, Karen Bell, Jeffrey A Liu, Zhijian Jiang, Yuansong Zhou, Hua Skene, Robert J Nie, Zhe |
| description | Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (
). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge
tools. KAI-11101 displayed an excellent
safety profile and showed neuroprotective properties in an
axon fragmentation assay as well as dose-dependent activity in a mouse PD model. |
| format | Article |
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). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge
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safety profile and showed neuroprotective properties in an
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). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge
tools. KAI-11101 displayed an excellent
safety profile and showed neuroprotective properties in an
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). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge
tools. KAI-11101 displayed an excellent
safety profile and showed neuroprotective properties in an
axon fragmentation assay as well as dose-dependent activity in a mouse PD model.</abstract><cop>United States</cop><pmid>39670820</pmid><orcidid>https://orcid.org/0000-0002-4798-6423</orcidid><orcidid>https://orcid.org/0009-0009-5125-8929</orcidid><orcidid>https://orcid.org/0009-0007-3802-6344</orcidid><orcidid>https://orcid.org/0000-0003-3306-9162</orcidid><orcidid>https://orcid.org/0000-0002-1482-6546</orcidid><orcidid>https://orcid.org/0000-0001-5737-2495</orcidid><orcidid>https://orcid.org/0000-0003-2112-1461</orcidid><orcidid>https://orcid.org/0000-0002-8310-0183</orcidid></addata></record> |
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| title | In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury |
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