2. Academic Validation
  3. Discovery of Novel MyD88 Inhibitor A5S to Alleviate Acute Lung Injury with Favorable Drug-like Properties

Discovery of Novel MyD88 Inhibitor A5S to Alleviate Acute Lung Injury with Favorable Drug-like Properties

  • J Med Chem. 2024 Dec 26;67(24):22263-22281. doi: 10.1021/acs.jmedchem.4c02401.
Pan Chen 1 2 3,  Yu Zou 1 2,  Xiemin Wang 1,  Zhichao Chen 1,  Ke Dong 1,  Jun Yang 1 2,  Yaqian Cui 1,  Jing Gu 4,  Xinyi Wu 1,  Xiaobo Li 1,  Ying Zhou 1,  Mi Guo 1,  Zhiwei Zheng 1 3,  Qi Chen 1,  Weiwei Zhu 1,  Di Wu 1,  Lina Yin 5,  Lingfeng Chen 5,  Qin Ouyang 4,  Guang Liang 1 2 3 5,  Qidong Tang 1 2 3
Affiliations

Affiliations

  • 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
  • 2 Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China.
  • 3 Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.
  • 4 Department of Medicinal Chemistry, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
  • 5 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 310053, China.
PMID: 39644263 DOI: 10.1021/acs.jmedchem.4c02401
Abstract

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 (L7) through virtual screening and synthesized twenty-seven L7 derivatives. An optimal compound (A5) was determined through enzyme-linked immunosorbent assay (ELISA), 2,5-diphenyl-2H-tetrazolium bromide (MTT), and biolayer interferometry (BLI) assay. The potent isomer A5S showed a high MyD88 binding ability and exerted an anti-inflammatory effect through the NF-κB/MAPK pathway. A5S 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, A5S 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, TJ-M2010-5, which is currently undergoing a Phase I study, and our previously reported MyD88 inhibitors LM8.

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