Bruceine B Displays Potent Antimyeloma Activity by Inducing the Degradation of the Transcription Factor c-Maf

  • ACS Pharmacol Transl Sci. 2023 Dec 5;7(1):176-185. doi: 10.1021/acsptsci.3c00222.
Hongyue Li  1  2 ,  Xiaoting Zhu  1  2 ,  Ziying Sun  2 ,  Qi Wang  1 ,  Shaojiang Song  3 ,  Yujia Xu  2 ,  Guisong He  4 ,  Xinliang Mao  1  2
Affiliations
  • 1. Institute of Clinical Pharmacology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
  • 2. Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, P. R. China.
  • 3. Department of Natural Medicinal Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 4. Department of Orthopaedics, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, P. R. China.
PMID: 38230274 DOI: 10.1021/acsptsci.3c00222
Abstract

The oncogenic transcription factor c-Maf has been proposed as an ideal therapeutic target for multiple myeloma (MM), a not-yet-curable malignancy of plasma cells. In the present study, we establish a c-Maf-based luciferase screen system and apply it to screen a homemade library composed of natural products from which bruceine B (BB) is identified to display potent antimyeloma activity. BB is a key ingredient isolated from the Chinese traditional medicinal plant Brucea javanica (L.) Merr. (Simaroubaceae). BB inhibits MM cell proliferation and induces MM cell Apoptosis in a caspase-3-dependent manner. The mechanism studies showed that BB inhibits c-Maf transcriptional activity and downregulates the expression of CCND2 and ITGB7, the downstream genes typically modulated by c-Maf. Moreover, BB induces c-Maf degradation via proteasomes by inducing c-Maf for K48-linked polyubiquitination in association with downregulated OTUB1 and USP5, two proven deubiquitinases of c-Maf. We also found that c-Maf activates STAT3 and BB suppresses the STAT3 signaling. In the in vivo study, BB displays potent antimyeloma activity and almost suppresses the growth of myeloma xenografts in 7 days but shows no overt toxicity to mice. In conclusion, this study identifies BB as a novel inhibitor of c-Maf by promoting its degradation via the ubiquitin-proteasomal pathway. Given the safety and the successful clinical application of bruceine products in traditional medicine, BB is ensured for further investigation for the treatment of patients with MM.

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