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Zinc finger transcription factor snail is a classical epithelial mesenchymal transition (EMT) inducing molecule. Snail has been widely reported to be highly expressed in a variety of malignant tumor tissues. The over expressed tumor cells generate EMT to obtain the invasion characteristics of stromal like cells and some characteristics of stem cells (this type of cells are called tumor stem cells or start cells, which generally have the ability of self-renewal, infinite proliferation and multi-directional differentiation, and can start the occurrence of tumors with high frequency) 。 At present, it is generally believed that snail regulates tumor invasion, metastasis, recurrence and drug resistance in the form of EMT dependence. Recently, it has been found that snail also promotes the proliferation and survival of tumor cells through EMT independent pathway. Its mechanism is that snail collects deacetylase HDAC1 / 2 to wild-type p53 protein, maintains the low acetylation level and protein expression level of p53, and then promotes the proliferation of wild-type p53 cells and inhibits their apoptosis. In view of the important role of snail protein in promoting tumor growth in situ, distant metastasis and recurrence, targeting the protein has potential therapeutic effect on malignant metastatic tumors. Traditionally, as a transcription factor, snail has been regarded as a "drug-resistant" target. It was found that a novel antitumor drug based on inhibiting the upstream regulatory pathway of snail and indirectly down regulating the expression level of snail has become one of the efforts in this field. However, there are some defects in these inhibitors, such as poor target selectivity and toxic side effects, which limit their further development. So far, there is no report on small molecular inhibitors targeting directly at snail.
On April 22, 2020, Professor Lu Tao and Professor Wu zhaoqiu of China Pharmaceutical University jointly published a research paper entitled "a potent CBP / P300 snail interaction inhibitor suppressors tumor growth and metastasis in wild type p53 expressing cancer" on science advanced, and found the first (first in class) small molecule inhibitor candidate drug directly targeting snail.
In this study, we first used the computational chemistry method to screen the fragments with the crystal structure of snail as the template, and scored the fragments with the strength of affinity. We found that the small molecular fragments with higher scores were pyrrole pyrimidine fragments. Then based on these fragments, we designed and synthesized 17 CYD series small molecular compounds that may have affinity with snail protein. Furthermore, computer simulation of molecular docking, biomembrane interference, biochemistry and molecular biology were used to find that cyd19 and the evolutionarily conserved 174 arginine (r174, the main binding site) of snail protein were efficiently bound by hydrogen bond and water release bond. It has been found that cyd19 can significantly inhibit the expression of snail protein in primary tumor cells and multiple tumor cell lines (without affecting mRNA level) at the level of tens of nanomoles. The molecular mechanism is that cyd19 interferes with the binding of acetyltransferase CBP / P300 and snail after binding with snail protein, resulting in the latter losing acetylation protection and being degraded by ubiquitin; cyd19 suppresses the signal pathway of snail ┨ p53 wt In addition, cyd19 had no significant effect on the function of vital organs and histomorphology of tumor bearing mice, suggesting that cyd19 had more toxic and side effects than cyd19 Small, with good development prospects (Figure 1).
Fig. 1. Antitumor molecular mechanism of cyd19 candidate compounds.
Cyd19, as a novel CBP / P300 snail protein interaction inhibitor, is the first reported antitumor growth and metastasis candidate compound targeting directly at snail. It has applied for two Chinese patents and one PCT international patent protection. The discovery of the first compound corrects the traditional recognition that snail is the target of "no medicine", which will provide a new choice for the treatment of malignant metastatic tumors (especially wild-type p53 malignant tumors), with important foundation and social significance. It is reported that the research team is fully promoting the preclinical research of cyd19 candidate compounds, and is expected to submit an application for clinical trials of new drugs of category 1.1 to the National Drug Administration (nmpa) in the near future.
Dr. Li Hongmei (post doctor in 2017), Bi Yanran (Master's degree 2019), Li Yang (doctor's degree 2018) and Fu Rong, associate professors of China Pharmaceutical University, are co first authors, and Prof. Lu Tao and Prof. Wu zhaoqiu are co correspondents. Professor Guo Qinglong and Professor Chen Yadong of China Pharmaceutical University, and Professor Wang Shui and Professor Xie Hui of the First Affiliated Hospital of Nanjing Medical University (Jiangsu People's Hospital) also made important contributions to this paper.
Brief introduction of Wu zhaoqiu research group
The research group is committed to the research of new anti-tumor targets and innovative drug discovery, and has made a series of achievements in the research of molecular mechanism of key proteins (i.e. EMT related transcription factors snail, ZEB1) promoting tumor growth and metastasis, and target drug discovery. In the past five years, he has published 7 research papers on authors of communication (co communication) in nature cell biology, science advances, Journal of clinical investigation, nature communications (2 papers) and other comprehensive or professional authoritative journals, and applied for 5 Chinese patents (2 authorized) and 1 PCT international patent.
Representative works published in recent 5 years (first author, * corresponding author)
1.Ting Ni#, Xiao-Yan Li#, Na Lu#, et al, Zhao-Qiu Wu*, Stephen J. Weiss*. Snail1-dependent p53 repression regulates expansion and activity of tumor-initiating cells in breast cancer. Nat Cell Biol, 2016,18:1221-1232.
2.Hong-Mei Li#, Yan-Ran Bi#, Yang Li#, Rong Fu#, et al, Tao Lu*, Zhao-Qiu Wu*. A potent CBP/p300-Snail interaction inhibitor suppresses tumor growth and metastasis in wild-type p53-expressing cancer. Sci Adv, 2020,6:1-17.
3.Rong Fu#, Yi Li#, Nan Jiang#, Bo-Xue Ren#, et al, Zhao-Qiu Wu*. Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies. J Clin Invest, 2020,130:1252-1270.
4.Rong Fu#, Wen-Cong Lv#, Ying Xu#, Mu-Yun Gong#, et al, Zhao-Qiu Wu*. Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis. Nat Commun, 2020,11:1-16.
5.Rong Fu#, Chen-Feng Han#, Ting Ni#, Lei Di#, et al, Zhao-Qiu Wu*. A ZEB1/p53 signaling axis in stromal fibroblasts promotes mammary epithelial tumors. Nat Commun, 2019,10:1-13.
6.Lei Di#, Li-Juan Liu#, Yong-Ming Yan#, et al, Yong-Xian Cheng*, Zhao-Qiu Wu*. Discovery of a natural small-molecule compound that suppresses tumor EMT, stemness and metastasis by inhibiting TGFβ/BMP signaling in triple-negative breast cancer. J Exp Clin Cancer Res, 2019,38:1-15.
7.Rong Fu#, Yi-Wei Zhang#, Hong-Mei Li#, et al, Zhao-Qiu Wu*. LW106, a novel indoleamine 2,3-dioxygenase 1 inhibitor, suppresses tumor progression by limiting stroma-immune crosstalk and cancer stem cell enrichment in tumor microenvironment. Br J Pharmacol, 2018,175:3034-3049.
Original link: https://advances.sciencemag.org/content/6/17/eaaw8500
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