Recently, a research result of a global leading computational drug discovery company and pharmaceutical enterprise, a partner of Viva, has successfully published a research featured on the cover of the "Journal of Medicinal Chemistry". Viva Biotech was fully involved in this project and contributed to the discovery and optimization of the active compound KAI-11101. This research titled "In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury" showcases the potential of a new DLK inhibitor KAI-11101 in the treatment of neurodegenerative diseases and neuronal injury, it also reveals the process of discovering and optimizing KAI-11101 through computational screening. Marking a successful drug discovery case driven by FEP (Free Energy Perturbation). Hua Zhou, senior Director of chemistry at Viva Biotech, and Dr. Yuansong Jiang, Director of chemistry at Viva Biotech, and Bioassay team participated in the testing, synthesis and optimization of the candidate compounds, providing key support for the successful development of KAI-11101.
(Source: ACS website)
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. In 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 role 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.
（Source: ACS）
In this highly challenging project, Viva Biotech is responsible for the entire synthesis work from project initiation to the discovery of the active compound KAI-11101. Since the target molecules were designed based on activity predictions from a computational platform, this placed high demands on the chemical diversity and route design of the synthesis work. With Viva chemists' extensive experience and efficient synthesis strategies also took advantage of photochemistry, glovebox platform, and electrochemistry technologies. This enabled the coverage of various chemical frameworks and the modification of different functional groups. Additionally, relying on powerful technical support platforms such as catalytic screening platform and quick turnaround SFC chiral preparation capabilities, Viva chemistry team significantly improved the iteration efficiency from computational prediction to experimental validation. This ensured the high-quality synthesis of each target molecule and strongly facilitated the entire process from the design to the discovery of KAI-11101. This project fully demonstrates Viva Biotech's professional capabilities and deep expertise in the small molecule synthesis.
Viva Biotech's chemistry team is led by highly experienced chemistry experts and collaborates with the top pharmaceutical companies. The team operate state-of-the-art facilities across multiple sites including Shanghai, Suzhou, Jiaxing, and Chengdu. Viva Biotech's chemistry services fully integrated drug discovery program alongside cutting-edge biology services and supported by advanced AI and computer-aided drug design platform. Viva Biotech offers comprehensive services in medicinal chemistry, synthetic chemistry, chemical analysis, and purification preparation. Its services cover the entire drug discovery process from hit discovery, and lead optimization to candidate screening, addressing various modalities, including small molecules, PROTACs, molecular glues, peptides, and ADCs. Up to now, Viva Biotech has completed over 200 projects from hit to lead optimization, advancing more than 50 compounds into clinical stages. By deeply integrating biological and chemical services, Viva Biotech continues to accelerate drug discovery, supporting global pharmaceutical innovation.
For more information, please refer to the full paper: Lagiakos HR, Zou Y, Igawa H, et al. In Silico enabled discovery of KAI-11101, a preclinical DLK inhibitor for the treatment of neurodegenerative disease and neuronal injury. Journal of Medicinal Chemistry. December 2024. doi:10.1021/acs.jmedchem.4c02074
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