It is now well appreciated that some bioactive small molecules exert their activities by acting as “molecular glues” that enhance protein-protein interaction to modulate their functions. An emerging theme in the field is that glues may not cause completely neomorphic interactions between protein pairs but rather enhance already existing low-affinity interactions. This finding raises key questions, such as whether there are physiologic consequences or regulatory mechanisms behind these low-affinity interactions and how increasing our understanding of this phenomenon can be leveraged to develop therapeutic tools for challenging targets.
In this ASPIRE award, Nicolas Thomä’s group will address these questions in the context of medulloblastomas (MBs), the most lethal childhood cancer. Next-generation sequencing has unveiled four molecular subgroups of MBs, but some subgroups remain poorly understood, hindering the development of effective treatments. The project will take three recent convergent findings into account. It has been shown that the somatic mutations that cause group 4 MB converge on the core binding factor alpha (CBFA) complex, which is key to transcriptional control. In addition, mutations in the ubiquitin ligase KBTBD4 have been identified as a driver in these subgroups. Finally, recent work has shown that the small molecule UM171 induces degradation of the CoREST complex by acting as a molecular glue between KBTBD4 and HDAC1, a member of the CoREST complex.
In this project, Thomä hypothesizes that MB mutations and UM171 induce KBTBD4-dependent CBFA degradation in a similar manner to CoREST degradation. They will elucidate the mechanistic basis by which KBTBD4 mutations promote CBFA degradation. The proposal outlines three aims: characterizing the substrates of KBTBD4 and their functional relevance to MB subgroups 3 and 4, conducting biochemical reconstitutions to determine direct interactions and ubiquitylation substrates, and examining the molecular and structural basis of these interactions. The study employs a multi-faceted approach combining cell biology, biochemistry, and structural biology to shed light on the complex interplay between KBTBD4, its substrates, and compounds like UM171. By understanding the molecular mechanisms underlying MB subgroups, the study aims to lay the foundation for future therapeutic interventions targeting KBTBD4 mutations, potentially offering new hope for children battling this deadly cancer.