| Autor: |
Zoran Rankovic, Gisele Nishiguchi, Sherif Abdelhamed, Sarah Young, Elizabeth Caine, Lauren Mascibroda, Jeffrey Kooijman, Sourav Das, Darcie Miller, Kevin McGowan, Anand Mayasundari, Zhe Shi, Juan Barajas, Ryan Hiltenbrand, Anup Aggarwal, Yunchao Chang, Vibhor Mishra, Ravi Kalathur, Junmin Peng, Shondra Pruett-Miller, Danette Daniels, Marjeta Urh, Anang Shelat, Charles Mullighan, Kristin Riching, Guido Zaman, Marcus Fischer, Jeffery Klco, Shilpa Narina, Allister Loughran, Anthony High |
| Rok vydání: |
2023 |
| DOI: |
10.21203/rs.3.rs-2883533/v1 |
| Popis: |
While the PROTAC approach to targeted protein degradation greatly benefits from rational design, the discovery of molecular glue degraders currently relies on screening strategies. Here, we describe screening of a library containing 3,630 cereblon binders against a panel of 9 patient-derived cancer cell lines. This led to the discovery of SJ7590, a potent degrader of CK1α, IKZF1 and IKZF3 proteins. Through a structure-guided optimization strategy we developed SJ3149, a uniquely potent and selective CK1α degrader. The crystal structure of the CK1α+CRBN+DDB1+SJ3149 quaternary complex provided a rationale for the improved degradation properties via direct contacts between SJ3149 and CK1α. In a panel of 115 human cancer cell lines SJ3149 displayed broad antiproliferative activity. This activity profile, which showed statistically significant correlation with MDM2 inhibitor Nutlin-3a, suggests potential for the development of treatments for hematological cancers, as well as solid tumors. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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