Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines.
Date
2024-01-16ICR Author
Author
Nishiguchi, G
Mascibroda, LG
Young, SM
Caine, EA
Abdelhamed, S
Kooijman, JJ
Miller, DJ
Das, S
McGowan, K
Mayasundari, A
Shi, Z
Barajas, JM
Hiltenbrand, R
Aggarwal, A
Chang, Y
Mishra, V
Narina, S
Thomas, M
Loughran, AJ
Kalathur, R
Yu, K
Zhou, S
Wang, X
High, AA
Peng, J
Pruett-Miller, SM
Daniels, DL
Urh, M
Shelat, AA
Mullighan, CG
Riching, KM
Zaman, GJR
Fischer, M
Klco, JM
Rankovic, Z
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Humans
Antineoplastic Agents
Cell Line
Neoplasms
Proteolysis
Ubiquitin-Protein Ligases
Research team
Targeted Protein Degrad
Language
eng
Date accepted
2023-12-21
License start date
2024-01-16
Citation
Nature Communications, 2024, 15 (1), pp. 482 -
Publisher
NATURE PORTFOLIO