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

  • Nat Commun. 2024 Jan 16;15(1):482. doi: 10.1038/s41467-024-44698-1.
Gisele Nishiguchi  #  1 ,  Lauren G Mascibroda  #  2 ,  Sarah M Young  #  1 ,  Elizabeth A Caine  3 ,  Sherif Abdelhamed  2 ,  Jeffrey J Kooijman  4 ,  Darcie J Miller  5 ,  Sourav Das  1 ,  Kevin McGowan  1 ,  Anand Mayasundari  1 ,  Zhe Shi  1 ,  Juan M Barajas  2 ,  Ryan Hiltenbrand  2 ,  Anup Aggarwal  1 ,  Yunchao Chang  2 ,  Vibhor Mishra  2 ,  Shilpa Narina  6 ,  Melvin Thomas  2 ,  Allister J Loughran  6 ,  Ravi Kalathur  5 ,  Kaiwen Yu  7 ,  Suiping Zhou  7 ,  Xusheng Wang  7 ,  Anthony A High  7 ,  Junmin Peng  5  7 ,  Shondra M Pruett-Miller  6  8 ,  Danette L Daniels  3 ,  Marjeta Urh  3 ,  Anang A Shelat  1 ,  Charles G Mullighan  2 ,  Kristin M Riching  3 ,  Guido J R Zaman  4 ,  Marcus Fischer  9 ,  Jeffery M Klco  10 ,  Zoran Rankovic  11
Affiliations
  • 1. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • 2. Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • 3. Promega Corporation, 5430 East Cheryl Drive, Madison, WI, 53711, USA.
  • 4. Oncolines B.V., Kloosterstraat 9, 5349 AB, Oss, The Netherlands.
  • 5. Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • 6. Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • 7. Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • 8. Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Memphis, TN, 38105, USA.
  • 9. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. [email protected].
  • 10. Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. [email protected].
  • 11. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. [email protected].
  • # Contributed equally.
PMID: 38228616 DOI: 10.1038/s41467-024-44698-1
Abstract

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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