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

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

Nature medicine (2019-12-04)
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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Phosphatase Inhibitor Cocktail 3, DMSO solution
Millipore
Anti-FLAG® M2 Magnetic Beads, affinity isolated antibody
Sigma-Aldrich
Bcl-xL Active human, recombinant, expressed in E. coli, ≥90% (SDS-PAGE)
Sigma-Aldrich
Protease Inhibitor Cocktail, for use with mammalian cell and tissue extracts, DMSO solution
Sigma-Aldrich
Apyrase from potato, recombinant, expressed in Pichia pastoris, ATPase ≥1000 units/mg protein, lyophilized powder
Sigma-Aldrich
Bcl-2 Active human, recombinant, expressed in E. coli, ≥80% (SDS-PAGE)
Sigma-Aldrich
Bcl-w (Minus C-Terminus) human, >95% (SDS-PAGE), recombinant, expressed in E. coli, buffered aqueous glycerol solution
Sigma-Aldrich
4-Hydroxymephenytoin, ≥98% (HPLC)
Sigma-Aldrich
Phenazine methosulfate
Sigma-Aldrich
DT2216, ≥90% (HPLC)
Sigma-Aldrich
MS-SAFE Protease and Phosphatase Inhibitor