Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-X

Xuan Zhang; Peiyi Zhang; Guangrong Zheng; Dinesh Thummuri; Yonghan He; Xingui Liu; Daohong Zhou

doi:10.1039/c9cc07217a

Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-X

Xuan Zhang, Peiyi Zhang, Guangrong Zheng, Dinesh Thummuri, Yonghan He, Xingui Liu, Daohong Zhou

Research output: Contribution to journal › Article › peer-review

57 Scopus citations

Abstract

BCL-X_L, an anti-apoptotic BCL-2 family protein, plays a key role in cancer cell survival. However, the potential of BCL-X_L as an anti-cancer target has been hampered by the on-target platelet toxicity because platelets depend on BCL-X_L to maintain their viability. Here we report the development of a PROTAC BCL-X_L degrader, XZ424, which has increased selectivity for BCL-X_L-dependent MOLT-4 cells over human platelets compared with conventional BCL-X_L inhibitors. This proof-of-concept study demonstrates the potential of utilizing a PROTAC approach to achieve tissue selectivity.

Original language	English (US)
Pages (from-to)	14765-14768
Number of pages	4
Journal	Chemical Communications
Volume	55
Issue number	98
DOIs	https://doi.org/10.1039/c9cc07217a
State	Published - 2019
Externally published	Yes

ASJC Scopus subject areas

Electronic, Optical and Magnetic Materials
General Chemistry
Ceramics and Composites
Metals and Alloys
Materials Chemistry
Surfaces, Coatings and Films
Catalysis

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title = "Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-X",

abstract = "BCL-XL, an anti-apoptotic BCL-2 family protein, plays a key role in cancer cell survival. However, the potential of BCL-XL as an anti-cancer target has been hampered by the on-target platelet toxicity because platelets depend on BCL-XL to maintain their viability. Here we report the development of a PROTAC BCL-XL degrader, XZ424, which has increased selectivity for BCL-XL-dependent MOLT-4 cells over human platelets compared with conventional BCL-XL inhibitors. This proof-of-concept study demonstrates the potential of utilizing a PROTAC approach to achieve tissue selectivity.",

author = "Xuan Zhang and Peiyi Zhang and Guangrong Zheng and Dinesh Thummuri and Yonghan He and Xingui Liu and Daohong Zhou",

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T1 - Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-X

AU - Zhang, Xuan

AU - Zhang, Peiyi

AU - Zheng, Guangrong

AU - Thummuri, Dinesh

AU - He, Yonghan

AU - Liu, Xingui

AU - Zhou, Daohong

N1 - Publisher Copyright: This journal is © The Royal Society of Chemistry.

PY - 2019

Y1 - 2019

N2 - BCL-XL, an anti-apoptotic BCL-2 family protein, plays a key role in cancer cell survival. However, the potential of BCL-XL as an anti-cancer target has been hampered by the on-target platelet toxicity because platelets depend on BCL-XL to maintain their viability. Here we report the development of a PROTAC BCL-XL degrader, XZ424, which has increased selectivity for BCL-XL-dependent MOLT-4 cells over human platelets compared with conventional BCL-XL inhibitors. This proof-of-concept study demonstrates the potential of utilizing a PROTAC approach to achieve tissue selectivity.

AB - BCL-XL, an anti-apoptotic BCL-2 family protein, plays a key role in cancer cell survival. However, the potential of BCL-XL as an anti-cancer target has been hampered by the on-target platelet toxicity because platelets depend on BCL-XL to maintain their viability. Here we report the development of a PROTAC BCL-XL degrader, XZ424, which has increased selectivity for BCL-XL-dependent MOLT-4 cells over human platelets compared with conventional BCL-XL inhibitors. This proof-of-concept study demonstrates the potential of utilizing a PROTAC approach to achieve tissue selectivity.

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Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-X

Abstract

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