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

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

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-44698-1

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