2. Academic Validation
  3. Optimization of novel quinazolinone derivatives as CRBN E3 ligase modulators for enhanced degradative activity and metabolic stability

Optimization of novel quinazolinone derivatives as CRBN E3 ligase modulators for enhanced degradative activity and metabolic stability

  • Bioorg Chem. 2026 Jul 5:175:109816. doi: 10.1016/j.bioorg.2026.109816.
Peng Chen 1,  Hongkang Peng 1,  Chen Liu 2,  Yuxiang Li 2,  Tong Yang 2,  Mohan Li 1,  Chengxuan Hu 3,  Shaojie Li 2,  Zihao Deng 2,  Zhen Wang 4,  Linyi Liu 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; NHC Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric, Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
  • 2 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
  • 3 School of computer, University of South China, Hengyang, Hunan 421001, China.
  • 4 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; NHC Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric, Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: zhenw@usc.edu.cn.
  • 5 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; NHC Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric, Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. Electronic address: liuly0734@usc.edu.cn.
PMID: 41936215 DOI: 10.1016/j.bioorg.2026.109816
Abstract

CRBN E3 Ligase modulators (CELMoDs) exhibit excellent pharmacological activity by degrading Cereblon (CRBN) associated multiple substrates and have become an important field for protein degradation drugs development. Previously, we conducted structural modifications on the quinazolinone-based CELMoD CC-122 to obtain derivative 1, which exhibited enhanced degradative activity, but it had issues with metabolic stability. Herein, we designed, synthesized and evaluated a series of novel quinazolinone derivatives, aiming to optimize degradative activity and metabolic stability. After multiple rounds of modification and screening, we obtained compound 26 (NHWL071065), which demonstrated significantly superior lymphoma cell proliferation inhibition and IKZF1/3 degradation activity compared to compound 1, and also showed a significant improvement in the stability of liver microsomes. Compound 26 demonstrates great potential for further research. This study has laid a solid foundation for us to develop novel CELMoDs with potential for becoming drugs.

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