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The latest achievements of the groups led by Zhang Jian and Yu Jianxiu, from Shanghai Jiao Tong University School of Medicine, were online published in international famous academic magazine “Nature Chemical Biology (IF=15.065) on July 24,whichrevealed the potential pathways of APC - Asef interaction to regulate colon cancer metastasis mechanism through designing thefirst inhibitor MAIT - 203targetingAPC - Asef protein interaction, opening up a new direction for the potential treatment of colon cancer metastasis. The paper is titled ”Peptidomimetic inhibitors of APC-Asef interaction block colorectal cancer migration“.
Colon cancer is the third most common cancer in the world, with a mortality rate of up to 60%, and the malignant metastasis is one of the main causes of high mortality in colon cancer patients. Adenomatous Polyposis Coli (APC) is a protein associated with the development of colon cancer. The recent clinical studies found that APC was abnormally boundtoAsef protein and continued to activate the guanylic acid activation factor in more than 80% of patients with malignant metastasis of colon cancer, which played an important role in the malignant metastasis of colon cancer. In order to explore whether APC - Asef protein interaction could be a target to blockmalignant metastasis of colon cancer, Zhang Jian etc. carried on the related research, and found that Asefbound the surface of more than 2500 broad flat pockets of APC-ARM through its ABR domain consisting of 25 residues. In order to overcome the large and shallow protein interaction pockets which is not easily to design its inhibitors, after developing the method of inducing the small molecule protein interaction, Zhang Jian etc.through inducing the APC residues‘ conformationturned large flat pockets which is hard to combine small molecules into a wide flat ring drug pockets in APC, and designed the first APC pocket inhibitors MAIT - 203 by optimizing the structure-based drug method. This series of inhibitors could selectively block - APC-Asef protein interaction, and had the maximum Ki value up to15nM, which was stronger than the APC-Asef protein interaction and would not affect the affinity of APCwith other proteins. Furthermore, they confirmed that the inhibitor could inhibite the malignant metastasis of colon cancer by destroying the APC-Asef protein. Using the inhibitor in their study, they also identified CDC42 was the direct downstream GTPase involved in the APC-Asef protein interaction, and then found that multiple APC - Asef protein interaction activating signaling pathways.
The next step of research will explore the APC - Asef protein interaction regulation pathways in colon cancer, and optimize the feasibility of lead compounds MAIT - 203 into medicinal properties to develop of new drug anti-malignant-colon-cancer-metastasis with low toxicity and high efficiency.
The development of drug design methods provides an effective breakthrough tool for new target identification and First-in-class drug discovery of major diseases. Since 2009, Zhang’s group has long been engaged in the design of the precise drugs associated with new targets, and has achieved a lot especially in the fields of drug design methods development, accurate target recognition and First - in - class drug discovery, who has been published a series of drug designs as the corresponding author in Nature ChemicalBiololgy, Chemical Reviews, Chemical Society Reviews, American Journal of Human Genetics, Nucleic Acids Research, Bioinformatics, Structure, the ACS Medical Chemistry Letters and many other important academic journals. This study is performed by Researcher Zhang Jian together with Researcher Yu Jianxiu, both of whom are corresponding authors, and Dr Deng Rong and DrJiang Hai-ming, and Dr. Yang Xiuyan are first authors. In addition, Pro. Chen Guoqiang and Pro. Wu Geng from Shanghai Jiao Tong University, Pro. Li Jian from East China University of Science and Technology, Pro. Qin Yue at the Chinese Academy of Science Shanghai Institute of Health, and Chen Yu at Chinese Academy of Science Shanghai Silicate Institutewere contributed to the paper.