Discovery of Novel MyD88 Inhibitor A5S to Alleviate Acute Lung Injury with Favorable Drug-like Properties
Myeloid differentiation primary response 88 (MyD88) plays a central role in inflammatory responses and diseases. However, only a few inhibitors of MyD88 with some limits have been reported currently. Herein, we identified a lead compound (<b>L7</b>) through virtual screening and synthesized twenty-seven <b>L7</b> derivatives. An optimal compound (<b>A5</b>) was determined through enzyme-linked immunosorbent assay (ELISA), 2,5-diphenyl-2<i>H</i>-tetrazolium bromide (MTT), and biolayer interferometry (BLI) assay. The potent isomer <b>A5S</b> showed a high MyD88 binding ability and exerted an anti-inflammatory effect through the NF-κB/MAPK pathway. <b>A5S</b> had good stability and safety, showed the highest distribution concentration in the lungs, and exhibited good therapeutic effects on LPS-induced and sepsis-induced ALI mouse models. Most importantly, <b>A5S</b> showed advantages in PK properties, and was identified as a promising MyD88 inhibitor with favorable drug-like properties, compared to the only approved MyD88 inhibitor, <b>TJ-M2010-5</b>, which is currently undergoing a Phase I study, and our previously reported MyD88 inhibitors <b>LM8</b>.
Authors
- Di Wu (ORCID: https://orcid.org/0000-0001-5492-6106)
- Lingfeng Chen (ORCID: https://orcid.org/0000-0003-0089-6559)
- Qidong Tang (ORCID: https://orcid.org/0000-0002-2045-4646)
- Ke Dong (ORCID: https://orcid.org/0000-0002-9773-6350)
- Yu Zou (ORCID: https://orcid.org/0000-0001-6678-6091)
- Ying Zhou (ORCID: https://orcid.org/0000-0002-6989-8352)
- Qin Ouyang (ORCID: https://orcid.org/0000-0002-1161-5102)
- Xiemin Wang
- Zhiwei Zheng (ORCID: https://orcid.org/0009-0008-7877-2226)
- Jing Gu (ORCID: https://orcid.org/0000-0001-5735-8482)
- Guang Liang (ORCID: https://orcid.org/0000-0002-8278-849X)
- Yaqian Cui
- Xiaobo Li (ORCID: https://orcid.org/0000-0002-2752-749X)
- Qi Chen (ORCID: https://orcid.org/0000-0001-5894-6331)
- Pan Chen (ORCID: https://orcid.org/0000-0001-6562-5296)
- Zhichao Chen (ORCID: https://orcid.org/0000-0003-2311-4345)
- Weiwei Zhu (ORCID: https://orcid.org/0000-0002-9969-2232)
- Mi Guo
- Lina Yin (ORCID: https://orcid.org/0009-0009-4384-6915)
- Jun Yang (ORCID: https://orcid.org/0000-0002-0080-0476)
- Xinyi Wu (ORCID: https://orcid.org/0000-0003-3288-7489)
Institutions
- Army Medical University (CN)
- Wenzhou Medical University (CN)
- First Affiliated Hospital of Wenzhou Medical University (CN)
- Medicina (PL)
- University of Chinese Academy of Sciences (CN)
- Hangzhou Medical College (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-07
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02401
- Citations
- 10
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 2.40
Funders
- Wenzhou Medical University
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Wenzhou Institute of Biomaterials and Engineering