Lei Xiaoguang research group of Peking University found the candidate drug molecules of anti-tumor natural products targeting p53 pathway through new mechanism

As one of the most famous tumor suppressor genes, TP53 encodes p53 protein, which controls a wide and flexible biological network and plays the role of genome guardian The deletion or mutation of TP53 gene is closely related to the formation and development of various cancers Due to the important role of p53 protein in tumor control, both pharmaceutical enterprises and scientific research circles are actively developing candidate anti-tumor drugs targeting p53 biological pathway Recently, Lei Xiaoguang group of Peking University has synthesized the most complex rhetidenone a molecule in the natural product rhetidenone family for the first time by using the bionic synthesis strategy, and further elucidated the target protein and biological action mechanism of rhetidenone F, which has the strongest antitumor activity in the family, by means of chemical biological means Of rhytidenone A and elucidation of mode of action of the cytoxicillidene F "was published in Angewandte Chemie International Edition (DOI: 10.1002 / anie 201914257) It was found that rhytidenonef, acting covalently on the cys92 site of PA28 γ, blocked the effective degradation of p53 protein, further led to the accumulation of p53 protein in cells, and finally activated Fas signaling pathway and caused tumor cell apoptosis This work revealed that as the first discovered small molecule inhibitor of PA28 γ, rhytidenonef, a natural product, is expected to become a new generation of anti-tumor candidate drug molecules targeting p53 signaling pathway; meanwhile, this molecule can also be used as a chemical probe to further study the new biological mechanism of p53 protein degradation pathway At present, Lei Xiaoguang group is actively promoting the research of translational medicine and the development of preclinical anti-tumor drugs Dr Yue Zongwei, a doctoral student of Lei Xiaoguang's research group, and Dr Lin Xiaojun, a postdoctoral student, are the co first authors of the paper, and Professor Lei Xiaoguang is the corresponding author In addition, Dr Chen Kaiqi, postdoctoral student of Thailand, Dr ittipon siridechakorn, and Professor khanitha pudhom of Chulalongkorn University of Thailand also made important contributions to this work This work is mainly supported by the key R & D plan of the Ministry of science and technology, the National Natural Science Foundation, the Beijing outstanding young scientists project, and the joint research center for life sciences of Tsinghua University Dr Lin Xiaojun is supported by the post doctoral program of Beijing University.