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

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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

Edité par CCSD ; American Chemical Society -

International audience. 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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