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Nishiguchi, Gisele; Mascibroda, Lauren G; Young, Sarah M; Caine, Elizabeth A; Abdelhamed, Sherif; Kooijman, Jeffrey J; Miller, Darcie J; Das, Sourav; McGowan, Kevin; Mayasundari, Anand; Shi, Zhe; Barajas, Juan M; Hiltenbrand, Ryan; Aggarwal, Anup; Chang, Yunchao; Mishra, Vibhor; Narina, Shilpa; Thomas, Melvin; Loughran, Allister J; Kalathur, Ravi; Yu, Kaiwen; Zhou, Suiping; Wang, Xusheng; High, Anthony A; Peng, Junmin; Pruett-Miller, Shondra M; Daniels, Danette L; Urh, Marjeta; Shelat, Anang A; Mullighan, Charles G; Riching, Kristin M; Zaman, Guido J R; Fischer, Marcus; Klco, Jeffery M; Rankovic, Zoran
Nature communications, 01/2024, Volume: 15, Issue: 1Journal Article
Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins. Through a structure-informed exploration of structure activity relationship (SAR) around this small molecule we develop SJ3149, a selective and potent degrader of CK1α protein in vitro and in vivo. The structure of SJ3149 co-crystalized in complex with CK1α + CRBN + DDB1 provides a rationale for the improved degradation properties of this compound. In a panel of 115 cancer cell lines SJ3149 displays a broad antiproliferative activity profile, which shows statistically significant correlation with MDM2 inhibitor Nutlin-3a. These findings suggest potential utility of selective CK1α degraders for treatment of hematological cancers and solid tumors.
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