A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity

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. HoughtonGuangcun Huang, Robert Hromas, Marina Konopleva, Guangrong Zheng, Daohong Zhou

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1938-1947
Number of pages10
JournalNature Medicine
Volume25
Issue number12
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'A selective BCL-X<sub>L</sub> PROTAC degrader achieves safe and potent antitumor activity'. Together they form a unique fingerprint.

Cite this