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The international famous journals American Journal of Human Genetics (AJHG, IF = 10.794) in 2017 published online first issue of the key laboratory of Shanghai jiaotong university school of medicine, cell differentiation and apoptosis zhang jian group in the latest achievements in the field of allosteric Proteome - scale study of protein allosteric regulation perturbed by somatic mutations in 7000 cancer genomes, and report its development through massive tumor genome allosteric mapping on protein structure accurately identify each type of the tumor target, the method of new and used the method found new targets PDE10A non-small cell lung cancer.
With the development of precision medical characteristic of the new targets to identify tumor subtypes have already become the important premise of the development of targeted drugs. Along with the all kinds of tumor patient clinical accumulating data of the genome, high intension data parsing tumor genome, to identify associated with each subtype of the tumor or the Driver of the tumor gene (Driver) genes and their expression protein, then the use of existing drugs or the development of new small molecules targeting the protein targets, provide individualized treatment for this type of patients has become a new trend of the era of precision medical drug discovery.
Allosteric (Allostery) refers to the far away from the Site of protein substrates Allosteric Site (the Allosteric Site) combined with the adjustment of small molecules, and thus the phenomenon of regulating protein substrates sites, is widely exist in organism and a regulating mechanism is very important. In this work, zhang jian to parse the 33 such tumors of 7000 cases of clinical patients genome, will identify the data mapping to more than 47000 mutations have been found on protein structure, found that these mutations in tumor genome in the sample is mainly enriched in protein allosteric site as well as the substrate of site. Based on this phenomenon, they designed according to the mapping on the distribution of the allosteric site of mutation to identify new targets for different tumors methods AlloDriver. Using this method, they found that the new target PDE10A non-small cell lung cancer (note: PDE10A is a known drug targets for the treatment of mental illness), and by the method of chemical biology proved PDE10A listed drugs can effectively kill non-small cell lung cancer cell lines, for the treatment of non-small-cell lung cancer (NSCLC) provides a new way.
Zhang jian group since 2009, has long-term commitment to the change in the field of drug discovery research, research in allosteric regulation mechanism to clarify, allosteric small design method development and the change of drug molecules found ways to make a series of work, with corresponding author in Chem Rev, Chem Soc Rev, Nucleic Acids Res, Bioinformatics, Structure, the ACS Med Chem Lett, and other important academic journals published a series of allosteric research results. The first author of this paper for the research of zhang jian and Dr Shen Qiancheng Cheng Fei from Harvard medical school in the United States, mutual corresponding author papers include professorZhao Zhongming at Vanderbilt university in the United States. In addition, Shanghai jiaotong university, professor Chen guoqiang, professorliumengyao at east China normal university, and Dr Lu Weijiang contributed to this paper.
The article links:http://dx.doi.org/10.1016/j.ajhg.2016.09.020