Lenalidomide, thalidomide and pomalidomide are the classical IMiDs (Immunomodulatory drugs) effective in the treatment of multiple myeloma and known to function via their ability to bind to Cereblon and recruit neosubstrates (IKZF1, IKZF3, SALL4, CK1α) for ubiquitination and subsequent proteosome-mediated degradation. Interestingly, only lenalidomide is capable of degrading casein kinase 1α (CK1α), resulting into a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q. However, in leukemia cells, lenalidomide achieves only partial degradation of CK1α, even at high concentrations and after long incubation time, limiting its utility for leukemia indications. Herein we will present the discovery of potent, selective and novel molecular glue degraders of CK1α in leukemia cells. By leveraging our library of cereblon modulators and phenotypically screening against multiple pediatric cancer cell lines, we identified compounds selective towards MOLM-13 cells. Profiling by Western blot and TMT-proteomics experiments enabled the identification of highly potent and selective degraders of CK1α displaying faster rates and superior levels of CK1α degradation relative to lenalidomide while sparing transcription factors IKZF1/3. The lead compound is also orally bioavailable in pharmacokinetics experiments in mice.

Discovery of selective, potent and orally bioavailable molecular glue degraders of casein kinase 1α (CK1α)

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.