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Potential therapeutic target in acute myeloid leukemia (AML): Geng et al. explore the development of molecular glue degraders (MGDs) targeting casein kinase 1 alpha (CK1α), a potential therapeutic target in AML.

The researchers synthesized over 100 glutarimide-containing compounds using cross-coupling and amide-coupling reactions. Through screening and optimization, they identified several potent and selective CK1α degraders, including QXG-6442.

Structure-activity relationship studies on the imidazo[1,2-a]pyridine scaffold of QXG-6442 revealed good tolerance for substituents, resulting in analogs with single-digit nanomolar activity. Molecular docking provided insights into key interactions between the degraders, CK1α, and CRBN.

The compounds demonstrated varying antiproliferative effects across cell lines, with AML cells showing the highest sensitivity. CK1α degradation led to stabilization of p53 and induction of p53-regulated genes. Global proteomics analysis confirmed the high selectivity of QXG-6442 for CK1α degradation. Additionally, selected compounds exhibited good microsomal stability, suggesting their potential as leads for further optimization.

This study provides new tool compounds for investigating CK1α degradation-dependent pharmacology and potential therapeutic strategies for AML.

The researchers used an IonOpticks Aurora Ultimate 25×75 C18 UHPLC column for high-resolution peptide separation in the proteomics analysis, enabling comprehensive profiling of degrader effects.

Publication
bioRxiv

Authors

Qixiang Geng, Zixuan Jiang, Woong Sub Byun, Katherine A. Donovan, Zhe Zhuang, Fen Jiang, Hannah M. Jones, Hlib Razumkov, Michelle T. Tang, Roman C. Sarott, Eric S. Fischer, Steven M. Corsello, Stephen M. Hinshaw, Nathanael S. Gray

Title

Development of potent and selective CK1α Molecular Glue Degraders