Discovery of CRBN-dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.
Hlib RazumkovZixuan JiangKheewoong BaekInchul YouQixiang GengKatherine Aleisha DonovanMichelle T TangRebecca J MetivierNada MageedPooreum SeoZhengnian LiWoong Sub ByunStephen P HinshawRoman C SarottEric S FischerNathanael S GrayPublished in: bioRxiv : the preprint server for biology (2024)
Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While Cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-01 derivatives that target casein kinase 1 alpha (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and a rationale for the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.
Keyphrases
- protein kinase
- acute myeloid leukemia
- protein protein
- small molecule
- single molecule
- multiple myeloma
- clinical trial
- emergency department
- insulin resistance
- metabolic syndrome
- skeletal muscle
- mass spectrometry
- tyrosine kinase
- high resolution
- quality improvement
- high throughput
- climate change
- oxidative stress
- living cells
- smoking cessation
- drug induced
- fluorescent probe
- weight loss
- heat shock protein
- human health
- glycemic control