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

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Identification of Potent, Selective, and Orally Bioavailable Small-Molecule GSPT1/2 Degraders from a Focused Library of Cereblon Modulators
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-05-27 , DOI: 10.1021/acs.jmedchem.0c01313
Gisele Nishiguchi ₁ , Fatemeh Keramatnia _{1,

2} , Jaeki Min ₁ , Yunchao Chang ₃ , Barbara Jonchere ₄ , Sourav Das ₁ , Marisa Actis ₁ , Jeanine Price ₁ , Divyabharathi Chepyala ₁ , Brandon Young ₁ , Kevin McGowan ₁ , P Jake Slavish ₁ , Anand Mayasundari ₁ , Jamie A Jarusiewicz ₁ , Lei Yang ₁ , Yong Li ₁ , Xiang Fu ₁ , Shalandus H Garrett ₁ , James B Papizan ₅ , Kiran Kodali ₆ , Junmin Peng _{6,

7,

8} , Shondra M Pruett Miller ₅ , Martine F Roussel ₄ , Charles Mullighan ₃ , Marcus Fischer _{1,

2,

8} , Zoran Rankovic ₁

Affiliation

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.

中文翻译：

从集中的小脑调节剂库中鉴定强效、选择性和口服生物可利用的小分子 GSPT1/2 降解物

虽然 PROTAC 目标蛋白降解方法极大地受益于合理设计，但小分子降解剂的发现主要依赖于表型筛选和回顾性目标识别工作。在这里，我们描述了针对一组患者来源的白血病和髓母细胞瘤细胞系的沙利度胺类似物的大型多样化文库的设计、合成和筛选。这些努力导致发现了有效且新颖的 GSPT1/2 降解剂，其对经典 IMiD 新底物（如 IKZF1/3）具有选择性，并在小鼠中具有高口服生物利用度。总之，本研究提供了化合物6 (SJ6986) 作为一种有价值的化学探针，用于研究 GSPT1/2在体外和体内的作用，并且它支持多种 CRBN 结合剂库的效用，以寻求针对不可成药的癌蛋白。

更新日期：2021-06-10

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