A Novel Compound 3a-M1, from Metabolites of Sinomenine Derivative 3a, Exerts Potent Anti-Aplastic Anemia Activity via IP3R/ORAI-Mediated CTL Ferroptosis

  • J Med Chem. 2025 May 8;68(9):9723-9740. doi: 10.1021/acs.jmedchem.5c00546.
Ziqian Zhang  1 ,  Xilan Ma  1 ,  Wei Pan  2 ,  Xiaoshun Li  1 ,  Yanyan Li  1 ,  Nan Fang  1 ,  Xin Yin  1 ,  Longlong Yang  1 ,  Qi Hou  1 ,  Dezhi Yang  1 ,  Tengfei Ji  1 ,  Ruifang Zheng  3 ,  Mingbao Lin  1
Affiliations
  • 1. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
  • 2. Center of Information, National Medical Products Administration, Beijing 100044, People's Republic of China.
  • 3. Xinjiang Key Laboratory of Uygur Medical Research, Xinjiang Institute of Materia Medica, Urumqi 841100, People's Republic of China.
PMID: 40243551 DOI: 10.1021/acs.jmedchem.5c00546
Abstract

Aplastic anemia (AA) is a refractory hematological disease with limited therapeutic effectiveness and serious treatment-related side effects. Cytotoxic T lymphocytes (CTLs) play a key role in AA pathogenesis. In our previous study, sinomenine derivative 3a was obtained, which demonstrated potential anti-AA activity by targeting CTLs with low toxicity. In this study, a novel metabolite, 3a-M1, was identified with optimized bioavailability from 3a metabolism, which exhibited a more notable effect in alleviating anemia symptoms, suppressing bone marrow CTLs activation, and improving hematopoietic function in immune-mediated bone marrow failure mouse models. In vitro experiments demonstrated that 3a-M1 directly inhibited CTLs activation and their killing function; the underlying mechanism was at least in part mediated by the selective Ferroptosis of overactivated CTLs via the IP3R/ORAI pathway. These findings suggest that 3a-M1 represents a novel potential therapeutic agent for AA treatment and Ferroptosis may serve as a promising target on CTLs for AA therapy.

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