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 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.