Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 11, Pages 7296-7311Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01313
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Funding
- NCI [P01 CA096832, P30 CA021765]
- Leukemia and Lymphoma Society Translational Research Program, NCI [R35 CA197695]
- Cancer Center Support Grant [CA012765]
- Alex's Lemonade Stand Foundation (ALSF)
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This study describes the design, synthesis, and screening of a large diverse library of thalidomide analogues against leukemia and medulloblastoma cell lines, leading to the discovery of potent GSPT1/2 degraders with selectivity over IMiD neosubstrates and high oral bioavailability in mice. Compound 6 (SJ6986) is proposed as a valuable tool for studying the role of GSPT1/2 and supports the utility of a diverse library of CRBN binders in targeting undruggable oncoproteins.
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.
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