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

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.

• Authors: 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
• Journal: Nature medicine (Nat Med) Vol. 25 Issue 12 Pg. 1938-1947 (12 2019) ISSN: 1546-170X [Electronic] United States
• PMID: 31792461 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Aniline Compounds
• Antineoplastic Agents
• BCL2L1 protein, human
• Sulfonamides
• bcl-X Protein
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, human
• navitoclax

Topics

• Aniline Compounds (chemistry, pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Blood Platelets (drug effects, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Heterografts
• Humans
• Mice
• Proteolysis
• Sulfonamides (chemistry, pharmacology)
• Thrombocytopenia (drug therapy, genetics, pathology)
• Von Hippel-Lindau Tumor Suppressor Protein (genetics)
• bcl-X Protein (antagonists & inhibitors, genetics)