2. Academic Validation
  3. Discovery of Novel Azaphenothiazine Derivatives to Suppress Endometrial Cancer by Targeting GRP75 to Impair Its Interaction with IP3R and Mitochondrial Ca2+ Homeostasis

Discovery of Novel Azaphenothiazine Derivatives to Suppress Endometrial Cancer by Targeting GRP75 to Impair Its Interaction with IP3R and Mitochondrial Ca2+ Homeostasis

  • J Med Chem. 2024 Aug 22;67(16):13829-13851. doi: 10.1021/acs.jmedchem.4c00638.
Xianwu Ling 1,  Jiahui Zhang 1,  Lingyi Song 1,  Huiwen Wu 1,  Qi Wang 1,  Xiaohu Liu 1,  Wei Ni 1,  Jian Li 1 2 3,  Yudong Wang 4 5,  Fei Mao 1
Affiliations

Affiliations

  • 1 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.
  • 2 Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832003, China.
  • 3 Key Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou 570228, China.
  • 4 Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
  • 5 Shanghai Municipal Key Clinical Specialty, Female Tumor Reproductive Specialty, Shanghai 200030, China.
PMID: 39082833 DOI: 10.1021/acs.jmedchem.4c00638
Abstract

Endometrial Cancer (EC) is the most common Cancer of the female reproductive tract, and there is an urgent need to develop new candidate drugs with good efficacy and safety to improve the survival rate and life quality of EC patients. Herein, a series of new azaphenothiazine derivatives were designed and synthesized and their anti-EC activities were evaluated. Among them, compound 33 showed excellent antiproliferative activities against both progesterone-sensitive ISK cells and progesterone-resistant KLE cells. Moreover, 33 could significantly inhibit colony formation and migration of EC cells and induce cell Apoptosis. Remarkably, 33 significantly suppressed KLE xenograft tumor growth without influencing body weights or key organs. In addition, 33 exhibited good pharmacokinetic properties and low extrapyramidal side effects. Mechanism research indicated that 33 reduced CA2+ levels in mitochondria by targeting GRP75 and disrupting its interaction with IP3R. Overall, 33 showed promising potential as an anti-EC candidate agent.

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