Molecular glues are small molecules that induce protein-protein interactions to modulate disease-relevant targets. While their potential as powerful therapeutics has been increasingly studied over the past decade, their discovery has largely been serendipitous, and paths for rational development are in their infancy. In this ASPIRE award, Brian Liau aims to transform molecular glue discovery through a genetics-first approach.
The Liau group recently demonstrated that the compound UM171 is a molecular glue that induces a neomorphic interaction between the E3 ligase KBTBD4 and the deacetylase HDAC1 of the CoREST complex. Interestingly, insertion mutations found in KBTBD4 in medulloblastoma also induce HDAC1 recruitment and CoREST degradation, and the inserted residues chemically mimic the position of the small molecule. This striking structural convergence between chemical and genetic neomorphs suggests that systematic insertional mutational scanning could reveal protein sites that are inherently “glue-able.” To capitalize on this insight, the team plans to develop a platform designed to map glueable sites across high-value oncology targets and ligase effectors.
To do so, they will apply deep insertion mutagenesis scanning to surface-exposed regions of cancer-amplified E3 ligases and transcription factors, generating mutant libraries expressed in cancer cells. The team will identify functional mutants that impact cell phenotype or protein stability using cell-based assays and sequencing, with follow-up characterization by co-immunoprecipitation mass spectrometry and functional genomics. If successful, this work will establish a systematic framework for identifying glueable sites, enabling the rational discovery of molecular glues that mimic neomorphic mutations. The outcome would represent a paradigm shift in drug discovery, providing new strategies to pursue targets that have long been considered undruggable.