Journal Article

Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines

Kooijman, Jeffrey J., Chang, Yunchao, Barajas, Juan M., Mascibroda, Lauren G., Mishra, Vibhor, High, Anthony A., Kalathur, Ravi, Shelat, Anang A., Wang, Xusheng, Rankovic, Zoran, Zhou, Suiping, Urh, Marjeta, Daniels, Danette L., Narina, Shilpa, Riching, Kristin M., Miller, Darcie J., Zaman, Guido J. R., Loughran, Allister J., Mullighan, Charles G., Caine, Elizabeth A., Thomas, Melvin, Young, Sarah M., McGowan, Kevin, Pruett-Miller, Shondra M., Peng, Junmin, Mayasundari, Anand, Abdelhamed, Sherif, Hiltenbrand, Ryan, Yu, Kaiwen, Fischer, Marcus, Klco, Jeffery M., Das, Sourav, Aggarwal, Anup, Shi, Zhe, Nishiguchi, Gisele

2024

Overview

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. Here, the authors describe a potent and selective CK1a molecular glue degrader with a broad antiproliferative potency. Crystallographic data provide rationale for the high degradation efficacy displayed by this compound.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/2 / 13/31 / 140/131 / 140/58 / 631/154/1435 / 631/45/474 / 631/45/535 / 82/83 / 96/1 / 96/98 / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Antiproliferatives / BASIC BIOLOGICAL SCIENCES / Blood cancer / Cancer / Cell Line / Crystallography / Degradation / Humanities and Social Sciences / Humans / MDM2 protein / multidisciplinary / Neoplasms - drug therapy / Proteins / Proteolysis / Science / Science & Technology - Other Topics / Science (multidisciplinary) / Solid tumors / Statistical analysis / Tumor cell lines / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism