Open AccessIdentification of Potent, Selective, and Orally Bioavailable Small-Molecule GSPT1/2 Degraders from a Focused Library of Cereblon Modulators
Author(s) -
Gisele Nishiguchi,
Fatemeh Keramatnia,
Jaeki Min,
Yunchao Chang,
Barbara Jonchère,
Sourav Das,
Marisa Actis,
Jeanine E. Price,
Divyabharathi Chepyala,
Brandon Young,
Kevin M. McGowan,
P.J. Slavish,
Anand Mayasundari,
Jamie A. Jarusiewicz,
Lei Yang,
Yong Li,
Xiang Dong Fu,
Shalandus H. Garrett,
James B. Papizan,
Kiran Kodali,
Junmin Peng,
Shondra Miller,
Martine F. Roussel,
Charles G. Mullighan,
Marcus Fischer,
Zoran Rankovic
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01313
Subject(s) - cereblon , chemistry , drug discovery , chemical library , small molecule , phenotypic screening , bioavailability , computational biology , in vivo , pharmacology , biochemistry , phenotype , biology , genetics , gene , ubiquitin ligase , ubiquitin
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.