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Identification of ubiquitination site in BCL-XL after PROTAC DT2216 treatment

ABSTRACT: The availability of a suitable lysine for PROTAC-mediated ubiquitination can also determine the degradative ability of a protein target and the selectivity of a PROTAC. PROTAC DT2216 selectively triggers ubiquitination and degradation of BCL-XL. In this study, we identify K87 is the key ubiquitinated lysine under DT2216 treatment through LC-MS/MS.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Disease Free

SUBMITTER: Dongwen Lv

LAB HEAD: Dongwen Lv

PROVIDER: PXD015454 | Pride | 2019-10-08

REPOSITORIES: Pride

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

Khan Sajid S Zhang Xuan X Lv Dongwen D Zhang Qi Q He Yonghan Y Zhang Peiyi P Liu Xingui X Thummuri Dinesh D Yuan Yaxia Y Wiegand Janet S JS Pei Jing J Zhang Weizhou W Sharma Abhisheak A McCurdy Christopher R CR Kuruvilla Vinitha M VM Baran Natalia N Ferrando Adolfo A AA Kim Yong-Mi YM Rogojina Anna A Houghton Peter J PJ Huang Guangcun G Hromas Robert R Konopleva Marina M Zheng Guangrong G Zhou Daohong D

Nature medicine 20191202 12

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 again ...[more]

PMID: 31792461

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