2. Academic Validation
  3. Design, synthesis, and activity evaluation of indole derivatives as potential stabilizers for p53 Y220C

Design, synthesis, and activity evaluation of indole derivatives as potential stabilizers for p53 Y220C

  • Bioorg Med Chem Lett. 2025 Jun 1:121:130161. doi: 10.1016/j.bmcl.2025.130161.
Linquan Li 1,  Xi Gu 2,  Jingyi Meng 3,  Yiming Wen 4,  Jing Yi 5,  Fengqian Xu 6,  Li Zhang 7,  Sulin Zhang 8,  Zhili Zuo 9
Affiliations

Affiliations

  • 1 School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong 643000, China; School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, UCAS, Hangzhou 310024, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4 School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, UCAS, Hangzhou 310024, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong 643000, China.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, UCAS, Hangzhou 310024, China; College of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, 610500, China.
  • 7 School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong 643000, China. Electronic address: zhangli@suse.edu.cn.
  • 8 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: slzhang@simm.ac.cn.
  • 9 School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong 643000, China; School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, UCAS, Hangzhou 310024, China. Electronic address: zlzuo@ucas.ac.cn.
PMID: 40057133 DOI: 10.1016/j.bmcl.2025.130161
Abstract

The p53 Y220C mutation is frequently observed in human cancers. This mutation renders the p53 Y220C unstable at physiological temperatures, leading to a loss of its normal function and promoting tumor development. In this study, a total of eight compounds were designed and synthesized based on the active compound C8. The protein thermal shift assay revealed that both C8-3b and C8-6 exhibited similar activity of C8, with a ΔTm value of +0.5 °C. Compounds C8-1a, C8-1b, and C8-2b were found to enhance the thermostability of p53 Y220C (ΔTm: + 1.0 °C), the melting temperature exhibits an enhancement of 0.5 °C over the C8, indicating that these compounds possess the ability to stabilize p53 Y220C. The results of the cell viability assay revealed that C8-1b exhibited selective inhibitory effects on the proliferation of tumor cells harboring the p53 Y220C mutation. Furthermore, we utilized molecular docking and two-dimensional interaction analysis to elucidate the binding mode and key interactions of these compounds with p53 Y220C. Our study suggests that these compounds could potentially serve as lead compounds for enhancing the stability of p53 Y220C, thus providing a rational approach for designing small molecule stabilizers against p53 mutations.

Keywords

Drug design; Structural modification; Synthesis; p53 Y220C.

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