2. Academic Validation
  3. Discovery of JN122, a Spiroindoline-Containing Molecule that Inhibits MDM2/p53 Protein-Protein Interaction and Exerts Robust In Vivo Antitumor Efficacy

Discovery of JN122, a Spiroindoline-Containing Molecule that Inhibits MDM2/p53 Protein-Protein Interaction and Exerts Robust In Vivo Antitumor Efficacy

  • J Med Chem. 2023 Dec 28;66(24):16991-17025. doi: 10.1021/acs.jmedchem.3c01815.
Jing Cheng 1 2,  Ziqin Yan 1,  Kailong Jiang 3,  Chen Liu 1 4,  Dehua Xu 3 5,  Xilin Lyu 1,  Xiaobei Hu 3,  Shiyan Zhang 1 2,  Yubo Zhou 1 3,  Jia Li 1 3 5,  Yujun Zhao 1 2 4 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, P. R. China.
  • 2 University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, P. R. China.
  • 3 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, P. R. China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China.
  • 5 School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124000, P. R. China.
  • 6 Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, P. R. China.
  • 7 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, P. R. China.
PMID: 38062557 DOI: 10.1021/acs.jmedchem.3c01815
Abstract

MDM2 and MDM4 cooperatively and negatively regulate p53, while this pathway is often hijacked by Cancer cells in favor of their survival. Blocking MDM2/p53 interaction with small-molecule inhibitors liberates p53 from MDM2 mediated degradation, which is an attractive strategy for drug discovery. We reported herein structure-based discovery of highly potent spiroindoline-containing MDM2 Inhibitor (-)60 (JN122), which also exhibited moderate activities against MDM4/p53 interactions. In a panel of Cancer cell lines harboring wild type p53, (-)60 efficiently promoted activation of p53 and its target genes, inhibited cell cycle progression, and induced cell Apoptosis. Interestingly, (-)60 also promoted degradation of MDM4. More importantly, (-)60 exhibited good PK properties and exerted robust antitumor efficacies in a systemic mouse xenograft model of MOLM-13. Taken together, our study showcases a class of potent MDM2 inhibitors featuring a novel spiro-indoline scaffold, which is promising for future development targeting Cancer cells with wild-type p53.

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