近日，标新生物和复旦大学谭文福团队在国际知名期刊《Biochemical Pharmacology》在线发表了题为“Sorafenib and SIAIS361034, a novel PROTAC degrader of BCL-xL, display synergistic antitumor effects on hepatocellular carcinoma with minimal hepatotoxicity”的文章，报道了靶向BCL-xL蛋白的PROTAC降解剂选择性降解肝癌细胞BCL-xL蛋白，当与索拉非尼联用时，在肝癌治疗中展现出优异的安全性和强效的抗肿瘤作用。
图1
BCL-xL是线粒体跨膜分子，是抗凋亡蛋白BCL-2家族蛋白成员，在线粒体凋亡调控中至关重要。研究团队首先比较了肿瘤公共数据库中两种抗凋亡蛋白BCL-xL和MCL-1的表达差异。BCL-xL mRNA的高表达水平与肝细胞癌患者的不良预后密切相关，与MCL-1相比，BCL-xL mRNA可能是肝细胞癌进展的一个更重要的指标。前期靶向BCL-xL和MCL-1联合治疗策略虽具有一定临床疗效，但存在明显肝毒性。因此，解决共靶向MCL-1和BCL-xL带来的肝毒副作用至关重要。
图2 BCL-xL过表达与肝癌不良预后有关
标新生物和谭文福团队在先前的研究中利用PROTAC技术开发了化合物SIAIS361034，能够选择性降解BCL-xL蛋白。研究团队首先考察了SIAIS361034和能够下调MCL-1的索拉非尼联合对肝癌细胞及正常肝细胞的抗增殖活性。结果表明，SIAIS361034联合索拉非尼可协同抑制肝癌细胞增殖，而对正常肝细胞无明显抗增殖活性。
图3 SIAIS361034联合索拉非尼对肝癌细胞具有较强联合药效，诱导肝癌细胞凋亡，但对正常肝细胞无明显毒性
为进一步评估SIAIS361034联合索拉非尼抗肿瘤作用影响，研究团队构建了肝癌的异种移植模型。证明了在联合索拉非尼时，靶向BCL-xL的PROTAC化合物在肝癌中具有优于传统小分子抑制剂的抗肿瘤活性，且耐受性更好。这可能归因于正常肝组织和肝癌细胞中CRBN的差异性表达，相比于正常组织，靶向BCL-xL的PROTAC分子更容易降解肝癌细胞中的BCL-xL，所以联合索拉非尼时并未表现出明显的毒性。
图4 SIAIS361034联合索拉非尼协同抑制肝癌移植瘤增殖，无明显肝肾毒性
总的来说，研究团队发现靶向BCL-xL的PROTAC化合物联合索拉非尼对肝癌具有优异抗肿瘤活性，相较于传统小分子抑制剂，具有较好的耐受性和安全性。
标新生物作为通讯单位与学术机构合作再发文章，进一步展示GlueTacs®平台上丰富的技术储备和转化潜力，也体现出该平台重要的学术价值和商业潜力。
《Biochemical Pharmacology》文章链接：
https://www.sciencedirect.com/science/article/pii/S0006295224005422
Recently, Gluetacs Therapeutics and Tan Wenfu lab from Fudan University published an article titled "Sorafenib and SIAIS361034, a novel PROTAC degrader of BCL-xL, display synergistic antitumor effects on hepatocellular carcinoma with minimal hepatotoxicity" online in the prestigious international journal Biochemical Pharmacology. The article reports that SIAIS361034, a PROTAC degrader targeting BCL-xL protein, selectively degrades BCL-xL protein in liver cancer cells. When combined with sorafenib, it exhibits excellent safety and potent antitumor effects in the treatment of hepatocellular carcinoma.
BCL-xL, a mitochondrial transmembrane molecule and a member of the anti-apoptotic BCL-2 family of proteins, plays a crucial role in regulating mitochondrial apoptosis. The research team first compared the expression differences between two anti-apoptotic proteins, BCL-xL and MCL-1, in tumor public databases. High expression levels of BCL-xL mRNA are closely related to poor prognosis in patients with hepatocellular carcinoma. Compared to MCL-1, BCL-xL mRNA may be a more important indicator of hepatocellular carcinoma progression. Although previous combined therapeutic strategies targeting BCL-xL and MCL-1 have shown some clinical efficacy, they are associated with significant hepatotoxicity. Therefore, addressing the hepatotoxic side effects resulting from co-targeting MCL-1 and BCL-xL is crucial.
In previous research, Gluetacs Therapeutics and Tan Wenfu lab developed the compound SIAIS361034 using PROTAC technology, which can selectively degrade BCL-xL protein. The research team first examined the anti-proliferative activity of SIAIS361034 in combination with sorafenib, which can downregulate MCL-1, on liver cancer cells and normal liver cells. The results showed that SIAIS361034 combined with sorafenib synergistically inhibited the proliferation of liver cancer cells but had no significant anti-proliferative activity against normal liver cells.
To further evaluate the antitumor effects of SIAIS361034 combined with sorafenib, the research team established a xenograft model of liver cancer. It has been demonstrated that PROTAC compounds targeting BCL-xL exhibit superior anti-tumor activity and better tolerability in liver cancer compared to traditional small molecule inhibitor when combined with sorafenib. This may be attributed to the differential expression of CRBN in normal liver tissue and liver cancer cells. Compared to normal tissue, PROTAC molecules targeting BCL-xL are more likely to degrade BCL-xL in liver cancer cells, so the combination of sorafenib did not show significant toxicity.
In summary, the research team found that the PROTAC compound targeting BCL-xL combined with sorafenib exhibits excellent antitumor activity against liver cancer, with better tolerability and safety compared to traditional small molecule inhibitor.
Gluetacs Therapeutics, by publishing this article with academic institutions as a corresponding affiliation, has once again demonstrated the rich technical reserve and translational potential of the GlueTacs® platform, as well as its significant academic valuation and commercial potential.
关于标新生物
标新生物自成立以来受到业内的广泛关注，2022-2024连续三年获得上海市科技型中小企业称号，2023、2024连续两年入选华医榜中国生物医药科技创新价值榜最具成长性小分子创新药企业TOP10，荣获2024专精特新中小企业和创新型中小企业称号、2024年度临港新片区科创新锐企业称号、2023上海市高价值专利运营大赛百强、2023中国海归创业大赛三等奖、2023临港杯第九届创青春上海青年创新创业大赛一等奖、2022浦东新区全球高校校友科创大赛二等奖、2022中国创新制药企业TOP10、2022第十一届中国创新创业大赛成长组全国赛优秀企业奖、2022第6届医疗健康投资卓悦榜年度生物医药最佳企业、2022第五届中国创翼创业创新大赛上海选拔赛浦东赛区十佳创翼奖、2022浦东新区全球高校校友科创大赛二等奖、2022Venture50新芽榜150强、2021年度全国颠覆性技术创新大赛优秀项目、2021年第二届生物产业年度攀登榜年度最具投资潜质的新锐BioTech、2021中国生物医药产业链创新风云榜金马奖最具关注度新锐企业TOP10奖项。公司陆续获得多项科技部和上海市科委资金支持，纳入临港新片区前沿产业优秀人才安家补贴、重点产业人才补贴、人才引进重点机构名单，知识产权管理体系获得中国专利保护协会认证，多位团队核心成员陆续获得临港新片区十大科技创新先锋人物、谈家桢生命科学产业化奖、杨雄科技创业奖、东方英才创业青年领军人才、上海高层次海外人才和上海市浦江人才等称号。公司也先后成为上海科技大学创新型硕士和工程博士培养单位，并先后与十多位海内外专家教授进行科研研究合作。
注：转载请注明出处，感谢您对标新生物的关注
