Design and development of IKZF2 and CK1α dual degraders Journal Article
| Authors: | Miyamoto, D. K.; Curnutt, N. M.; Park, S. M.; Stavropoulos, A.; Kharas, M. G.; Woo, C. M. |
| Article Title: | Design and development of IKZF2 and CK1α dual degraders |
| Abstract: | Lenalidomide achieves its therapeutic efficacy by recruiting and removing proteins of therapeutic interest through the E3 ligase substrate adapter cereblon. Here, we report the design and characterization of 81 cereblon ligands for their ability to degrade the transcription factor Helios (IKZF2) and casein kinase 1 alpha (CK1α). We identified a key naphthamide scaffold that depleted both intended targets in acute myeloid leukemia MOLM-13 cells. Structure-activity relationship studies for degradation of the desired targets over other targets (IKZF1, GSPT1) afforded an initial lead compound DEG-35. A subsequent scaffold replacement campaign identified DEG-77, which selectively degrades IKZF2 and CK1α, and possesses suitable pharmacokinetic properties, solubility, and selectivity for in vivo studies. Finally, we show that DEG-77 has antiproliferative activity in the diffuse large B cell lymphoma cell line OCI-LY3 and the ovarian cancer cell line A2780 indicating that the dual degrader strategy may have efficacy against additional types of cancer. © 2023 American Chemical Society |
| Keywords: | lenalidomide; ovarian neoplasms; metabolism; ubiquitin protein ligase; protein degradation; cell line, tumor; ovary tumor; tumor cell line; ubiquitin-protein ligases; ikaros transcription factor; proteolysis; humans; human; female; casein kinase ialpha; ikzf2 protein, human |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 66 |
| Issue: | 24 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 2023-12-28 |
| Start Page: | 16953 |
| End Page: | 16979 |
| Language: | English |
| DOI: | 10.1021/acs.jmedchem.3c01736 |
| PUBMED: | 38085607 |
| PROVIDER: | scopus |
| PMCID: | PMC11302056 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Source: Scopus |
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