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.
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / metabolism
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Apoptosis / drug effects
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Blood Platelets / cytology
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Blood Platelets / drug effects
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Blood Platelets / metabolism
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Cell Line, Tumor
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Humans
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Isoquinolines / chemistry*
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Isoquinolines / metabolism
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Isoquinolines / pharmacology
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Protein Binding
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Thalidomide / analogs & derivatives*
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Thalidomide / chemistry
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Thalidomide / metabolism
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Thalidomide / pharmacology
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Ubiquitin-Protein Ligases
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bcl-X Protein / antagonists & inhibitors
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bcl-X Protein / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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CRBN protein, human
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Isoquinolines
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bcl-X Protein
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Thalidomide
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pomalidomide
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Ubiquitin-Protein Ligases