Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives
Year: 2020
Type: review
Abstract: Blocking the MDM2/X-P53 protein-protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers. Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2-P53 interaction in 1996, SAR405838, NVP-CGM097, MK-8242, RG7112, RG7388, DS-3032b, and AMG232 currently undergo clinical evaluation for cancer therapy. This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera (PROTAC) degraders with a particular focus on how these inhibitors or degraders are identified from starting points, strategies employed, structure-activity relationship (SAR) studies, binding modes or co-crystal structures, biochemical data, mechanistic studies, and preclinical/clinical studies. Moreover, we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition, acquired resistance and toxicity of P53 activation as well as future directions.
Source: Acta Pharmaceutica Sinica B
Authors: Yuan Fang, Guochao Liao, Bin Yu
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,600
Funders: National Natural Science Foundation of China, China Postdoctoral Science Foundation, Nanjing University, State Key Laboratory of Pharmaceutical Biotechnology, Guangdong Provincial Key Laboratory for Translational Cancer Research of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangdong Province Higher Vocational Colleges and Schools Pearl River Scholar Funded Scheme
OpenAlex ID: W2999596427