Abstract
Whereas the PROTAC approach to target protein degradation greatly benefits from rational design, the discovery of small-molecule degraders relies mostly on phenotypic screening and retrospective target identification efforts. Here, we describe the design, synthesis, and screening of a large diverse library of thalidomide analogues against a panel of patient-derived leukemia and medulloblastoma cell lines. These efforts led to the discovery of potent and novel GSPT1/2 degraders displaying selectivity over classical IMiD neosubstrates, such as IKZF1/3, and high oral bioavailability in mice. Taken together, this study offers compound 6 (SJ6986) as a valuable chemical probe for studying the role of GSPT1/2 in vitro and in vivo, and it supports the utility of a diverse library of CRBN binders in the pursuit of targeting undruggable oncoproteins.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry*
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Administration, Oral
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Animals
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Binding Sites
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Cell Line, Tumor
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Half-Life
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Humans
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Ikaros Transcription Factor / metabolism
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Mice
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Molecular Dynamics Simulation
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Peptide Termination Factors / metabolism*
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Proteolysis / drug effects*
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Retrospective Studies
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Small Molecule Libraries / administration & dosage
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / metabolism
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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Thalidomide / administration & dosage
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Thalidomide / analogs & derivatives
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Thalidomide / metabolism
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Thalidomide / pharmacology
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Ubiquitin-Protein Ligases / chemistry*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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CRBN protein, human
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IKZF1 protein, human
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Peptide Termination Factors
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Small Molecule Libraries
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peptide-chain-release factor 3
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Ikaros Transcription Factor
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Thalidomide
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Ubiquitin-Protein Ligases