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The Development of New Spirooxindoles Targeting the p53–MDM2 Protein-Protein Interactions for Cancer Therapy

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Targeting Protein-Protein Interactions by Small Molecules

Abstract

Spiro compounds have drawn ever-increasing attention in drug discovery because of its prevalence in natural products/drugs and unique 3D structural features. A large number of spiro compounds have been proved to possess diverse bioactivities, and some of them have advanced into clinical trials for the treatment of diseases. The interruption of MDM2–p53 protein-protein interactions has been highly pursued as an attractive therapeutic strategy for cancer therapy. A large number of small-molecule inhibitors have been identified based on the well-defined MDM2–p53 interactions. Currently, several small-molecule inhibitors such as SAR405838, APG-115, MK-8242, DS-3032b, NVP-CGM097, RG7112, RG7388, and AMG 232 are undergoing clinical assessment for cancer therapy. In this chapter, we focus on the identification of spirooxindole containing small-molecule inhibitors (SAR405838, APG-115, RG7388, RO8994, RO2468, and RO5353), strategies employed for optimizations, structure–activity relationship studies (SARs) as well as their biochemical profiles. The identification of these lead compounds makes spirooxindoles promising scaffolds in designing potent inhibitors targeting MDM2–p53 interactions. Based on the SARs and the co-crystal structures of p53–MDM2 complexes, we first tentatively propose the prolinamide-based ‘3+1’ model for designing potential MDM2 inhibitors.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81430085, 21372206, and 81703326, National Key Research Program of Proteins (No. 2016YFA0501800), Key Research Program of Henan Province (No. 1611003110100), Scientific Program of Henan Province (No. 182102310123), China Postdoctoral Science Foundation (No. 2018M630840), Key Research Program of Higher Education of Henan Province(No.18B350009), and the Starting Grant of Zhengzhou University (No. 32210533).

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  1. Ministry of Education, Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan, China

    Bin Yu & Hong-Min Liu

  2. Co-innovation Center of Henan Province for New Drug Research & Development and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan, China

    Bin Yu & Hong-Min Liu

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Correspondence to Hong-Min Liu .

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  1. School of Pharmacy, Second Military Medical University, Shanghai, China

    Chunquan Sheng

  2. College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA

    Gunda I. Georg

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Yu, B., Liu, HM. (2018). The Development of New Spirooxindoles Targeting the p53–MDM2 Protein-Protein Interactions for Cancer Therapy. In: Sheng, C., Georg, G. (eds) Targeting Protein-Protein Interactions by Small Molecules. Springer, Singapore. https://doi.org/10.1007/978-981-13-0773-7_8

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