2. Academic Validation
  3. Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines

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

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. marcus.fischer@stjude.org.
  • 10 Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. jeffery.klco@stjude.org.
  • 11 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. zoran.rankovic@stjude.org.
  • # 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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