Identification of Potent, Selective, and Orally Bioavailable Small-Molecule GSPT1/2 Degraders from a Focused Library of Cereblon Modulators

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...

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Published in:Journal of medicinal chemistry Vol. 64; no. 11; p. 7296
Main Authors: Nishiguchi, Gisele, Keramatnia, Fatemeh, Min, Jaeki, Chang, Yunchao, Jonchere, Barbara, Das, Sourav, Actis, Marisa, Price, Jeanine, Chepyala, Divyabharathi, Young, Brandon, McGowan, Kevin, Slavish, P Jake, Mayasundari, Anand, Jarusiewicz, Jamie A, Yang, Lei, Li, Yong, Fu, Xiang, Garrett, Shalandus H, Papizan, James B, Kodali, Kiran, Peng, Junmin, Pruett Miller, Shondra M, Roussel, Martine F, Mullighan, Charles, Fischer, Marcus, Rankovic, Zoran
Format: Journal Article
Language:English
Published: 10.06.2021
ISSN:1520-4804, 1520-4804
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Summary: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.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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ISSN:1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.0c01313