小柯机器人

美国佛罗里达大学Daohong Zhou和Guangrong Zheng团队合作发现选择性的BCL-X_L蛋白水解靶向嵌合体（PROTAC）降解剂具有安全有效的抗肿瘤活性。12月2日，国际知名学术期刊《自然—医学》在线发表了这一成果。

为了降低ABT263（靶向BCL-X_L抑制剂）的毒性，研究人员将其改造为DT2216，这是一种人B细胞淋巴瘤-X_L （BCL-X_L）蛋白水解靶向嵌合体（PROTAC），将BCL-X_L靶向Von Hippel-Lindau（VHL）E3连接酶进行降解。体外实验表明DT2216对各种BCL-X_L依赖的白血病和癌细胞具有更强的杀伤力，但对血小板毒性却比ABT263小得多，这是因为VHL在血小板中的表达较少。在体内，DT2216无论是作为单一用药或与其他化疗药联合使用，都可有效抑制多种异种移植瘤的生长，但不会引起明显的血小板减少症。这些发现证明了使用PROTAC降低靶标药物毒性并为之前不可用药的靶点提供了治疗的前景。此外，DT2216可以开发为靶向BCL-X_L安全的一线抗癌药。

据了解，BCL-X_L是经过充分验证的癌症靶点。然而，针对该靶点和剂量依赖的血小板减少症限制了BCL-X_L抑制剂（例如ABT263）作为安全有效的抗癌药的使用。

附：英文原文

Title: A selective BCL-X L PROTAC degrader achieves safe and potent antitumor activity

Author: Sajid Khan, Xuan Zhang, Dongwen Lv, Qi Zhang, Yonghan He, Peiyi Zhang, Xingui Liu, Dinesh Thummuri, Yaxia Yuan, Janet S. Wiegand, Jing Pei, Weizhou Zhang, Abhisheak Sharma, Christopher R. McCurdy, Vinitha M. Kuruvilla, Natalia Baran, Adolfo A. Ferrando, Yong-mi Kim, Anna Rogojina, Peter J. Houghton, Guangcun Huang, Robert Hromas, Marina Konopleva, Guangrong Zheng, Daohong Zhou

Issue&Volume: 2019-12-02

Abstract: B-cell lymphoma extra large (BCL-XL) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-XL inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-XL proteolysis-targeting chimera (PROTAC), that targets BCL-XL to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-XL-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-XL.

DOI: 10.1038/s41591-019-0668-z

Source: https://www.nature.com/articles/s41591-019-0668-z

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex