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

Producción científica: Article › revisión exhaustiva

74 Citas (Scopus)

Resumen

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.

Idioma original	English (US)
Páginas (desde-hasta)	14765-14768
Número de páginas	4
Publicación	Chemical Communications
Volumen	55
N.º	98
DOI	https://doi.org/10.1039/c9cc07217a
Estado	Published - 2019
Publicado de forma externa	Sí

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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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.",

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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

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