新型MyD88抑制剂靶向治疗肝细胞癌及其机理

随着TLR/MyD88信号通路的研究深入，MyD88在肝细胞癌发生发展中的促进作用不断阐明。以MyD88为靶点寻求治疗肝细胞癌的研究已经成为国际研究热点。经过多年的创新研究，我们合成了具有自主知识产权的氨基噻唑类小分子化合物MyD88抑制剂。我们之前的研究发现该抑制剂不仅对肝癌细胞系H22细胞的增殖有抑制作用，而且还对H22活体肿瘤中的巨噬细胞具有调控作用。还发现MyD88抑制剂能够抑制AOM/DSS介导的结肠炎，改变致瘤微环境，使结肠癌发生率从100%降为零（该项成果发表在JNCI上）。于是我们设计此课题，探讨MyD88抑制剂在直接治疗肝细胞癌中的作用，并在MyD88抑制剂抑制肿瘤细胞增殖和调控局部免疫微环境两方面进行深入的机制探究，为进一步的临床应用奠定理论基础。

The TLR/MyD88 signaling pathway plays a critical role in the driving of inflammation and cancer. Recent researches suggested that hepatocellular carcinoma expression higher MyD88 which promoted the tumor growth and metastasis. To seek an inhibitor targeting the signaling in treating hepatocellular carcinoma has become a global hotspot. Therefore, we spent many years to search for MyD88 inhibitor, and successfully created and synthesized a novel thiazaol-aminoramification MyD88 inhibitor named TJ-M2010-5. We found that this MyD88 inhibitor suppressed the proliferation of murine hepatocellular carcinoma H22 cells and regulated different type of macrophages balance in tumor microenvironment. Our previous studies suggested that MyD88 inhibitor TJ-M2010-5 prevents AOM/DSS induced inflammation related colorectal cancer (published in JNCI). We conducted a series of experiments to search for more details about the directly treating effects of MyD88 inhibitor TJ-M2010-5 to H22 cell-induced hepatocellular carcinoma. And we explore the mechanisms of MyD88 inhibitor TJ-M2010-5 on cell proliferation and tumor microenvironment. We wish this project may lay foundation for further clinical applications of MyD88 inhibitor TJ-M2010-5 in treating hepatocellular carcinoma.