Design, Synthesis, and Biological Evaluation of a MyD88-Targeted Molecular Glue d21 for the Treatment of Acute Lung Injury

  • J Med Chem. 2026 Jun 25;69(12):14722-14740. doi: 10.1021/acs.jmedchem.6c00755.
Luxiao Zhu  1  2 ,  Dan Tang  1 ,  Ting Chen  3 ,  Chenhui Sun  1  2 ,  Ke Dong  1 ,  Qi Chen  1 ,  Qinxue Dai  3 ,  Yunchang Mo  3 ,  Pan Chen  4 ,  Jinfeng Sun  5 ,  Guang Liang  1  4  5  2 ,  Qidong Tang  1  5  3
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 325024, China.
  • 3. Department of Anesthesiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.
  • 4. School of Pharmacy, Hangzhou Medical College, Hangzhou 311399, China.
  • 5. Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University College of Pharmacy, Yanji 133002, Jilin, China.
PMID: 42284437 DOI: 10.1021/acs.jmedchem.6c00755
Abstract

Myeloid differentiation factor 88 (MyD88) is a critical mediator of inflammatory signaling. However, the development of MyD88 inhibitors has been limited, and there are no reports on MyD88 degraders. Based on our previously identified MyD88 Inhibitor c17 and employing a template-assisted modification strategy, we designed and synthesized 40 novel derivatives, and identified the optimal compound d21, which could inhibit nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway activation by facilitating the interaction between ring finger protein 126 (RNF126) (an E3 ubiquitin Ligase) and MyD88, thereby promoting ubiquitination and subsequent degradation of MyD88. The subacute toxicity test indicated that d21 had good safety profile. Furthermore, it demonstrated significant anti-inflammatory effects in both cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) induced acute lung injury (ALI) models, effectively ameliorating ALI symptoms. These findings suggest that d21 holds considerable promise as a MyD88-targeting molecular glue degrader for the treatment of ALI.

Products