2. Academic Validation
  3. Developing patient-derived organoids to demonstrate JX24120 inhibits SAMe synthesis in endometrial cancer by targeting MAT2B

Developing patient-derived organoids to demonstrate JX24120 inhibits SAMe synthesis in endometrial cancer by targeting MAT2B

  • Pharmacol Res. 2024 Sep 16:209:107420. doi: 10.1016/j.phrs.2024.107420.
Chunxue Zhang 1,  Xiaojing Lu 1,  Ting Ni 1,  Qi Wang 2,  Xiaoyan Gao 1,  Xiao Sun 1,  Jian Li 2,  Fei Mao 3,  Jin Hou 4,  Yudong Wang 5
Affiliations

Affiliations

  • 1 Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai 200030, China.
  • 2 State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • 3 State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: maofei@ecust.edu.cn.
  • 4 National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai 200433, China. Electronic address: houjin@immunol.org.
  • 5 Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai 200030, China. Electronic address: wangyudong@shsmu.edu.cn.
PMID: 39293586 DOI: 10.1016/j.phrs.2024.107420
Abstract

Endometrial Cancer (EC) is one of the most common gynecologic malignancies, which lacking effective drugs for intractable conditions or patients unsuitable for surgeries. Recently, the patient-derived organoids (PDOs) are found feasible for Cancer research and drug discoveries. Here, we have successfully established a panel of PDOs from EC and conducted drug repurposing screening and mechanism analysis for Cancer treatment. We confirmed that the regulatory β subunit of methionine adenosyltransferase (MAT2B) is highly correlated with malignant progression in endometrial Cancer. Through drug screening on PDOs, we identify JX24120, chlorpromazine derivative, as a specific inhibitor for MAT2B, which directly binds to MAT2B (Kd = 4.724 μM) and inhibits the viability of EC PDOs and canonical cell lines. Correspondingly, gene editing assessment demonstrates that JX24120 suppresses tumor growth depending on the presence of MAT2B in vivo and in vitro. Mechanistically, JX24120 induces inhibition of S-adenosylmethionine (SAMe) synthesis, leading to suppressed mTORC1 signaling, abnormal energy metabolism and protein synthesis, and eventually Apoptosis. Taken together, our study offers a novel approach for drug discovery and efficacy assessment by using the PDOs models. These findings suggest that JX24120 may be a potent MAT2B inhibitor and will hopefully serve as a prospective compound for endometrial Cancer therapy.

Keywords

3-Methyladenine (PubChem CID: 135398661); Endometrial cancer; JX24120; MAT2B; N-Acetylcysteine ethyl ester (PubChem CID: 6180); Necrostatin-1 (PubChem CID: 2828334); Patient-derived organoid; S-adenosylmethionine; S-adenosylmethionine (PubChem CID: 45072193); Z-VAD-FMK (PubChem CID: 87146076); chlorpromazine derivative.

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