In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-12-13 DOI:10.1021/acs.jmedchem.4c02074

H. Rachel Lagiakos, Yefen Zou, Hideyuki Igawa, Eric Therrien, Morgan Lawrenz, Mitsunori Kato, Mats Svensson, Felicia Gray, Kristian Jensen, Markus K. Dahlgren, Robert D. Pelletier, Karen Dingley, Jeffrey A. Bell, Zhijian Liu, Yuansong Jiang, Hua Zhou, Robert J. Skene, Zhe Nie

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Abstract

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 (59). 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 in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.