Identification of potent, selective, and orally bioavailable small-molecule GSPT1/2 degraders from a focused library of cereblon modulators
G Nishiguchi, F Keramatnia, J Min… - Journal of medicinal …, 2021 - ACS Publications
G Nishiguchi, F Keramatnia, J Min, Y Chang, B Jonchere, S Das, M Actis, J Price…
Journal of medicinal chemistry, 2021•ACS PublicationsWhereas 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 …
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 …
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.
ACS Publications