Final Report Summary - DRUGE3CRLS (Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases)
The ERC grant DrugE3CRL was centered on the development and application of chemical tools to probe molecular recognition of the Cullin RING ligases (CRLs), a class of multisubunit protein complexes that were previously considered undruggable targets by conventional drug discovery approaches. CRLs play crucial roles in regulating protein homeostatis and cellular physiology and pathophysiology, making them attractive targets in their own right. In addition, CRLs can be recruited to target proteins they do not normally interact with, to induce their degradation.
The project focused on two representative members of CRLs: 1) the von Hippel-Lindau protein (VHL), which forms part of a Cullin 2 ligase complex; and 2) the suppressor of cytokine signalling 2 (SOCS2) protein, which is a component of a Cullin 5 ligase complex. The P.I. and his team deployed innovative chemistry approaches to target these complexes. Their findings have demonstrated that it is possible to identify small molecules that bind to multiple binding sites and protein-protein interfaces on these proteins. Structural and biophysical elucidation of key non-covalent interactions guided the elaboration of the first series of small molecules targeting the VHL and SOCS2 E3 ligases as useful chemical tools to modulate the interactions and consequently study the biological function of these important E3 ligases. In particular, the work on VHL has led to the development of potent and selective inhibitors series of the interaction of VHL with targets such as HIF1alpha, resulting in HIF1alpha being acutely stabilised inside cells, an outcome of important pharmacological consequences. The P.I. has taken this system one step further and helped to pioneer the “PROTAC” approach, in which bifunctional ligands are created of the VHL ligand conjugated to another moiety that targets a cellular protein, thereby labelling that protein for degradation. The P.I. laboratory has made significant contributions in this area, including elucidating unprecedented structural and mechanical insights into the molecular recognition and mechanism of action of PROTAC molecules, and providing proof-of-concept of inducing an E3 ligase to self-destroy itself via chemically-induced dimerization (which they called homo-PROTAC).
In summary, the discoveries of this ERC grant have demonstrated that CRLs can be targeted successfully to yield cell-active chemical probes. Importantly, this research ushered a revolutionary new approach to modern drug discovery that is to target specific proteins for degradation, for example unwanted disease-realted proteins. This approach is transforming conventional small-molecule drug discovery and is seeing mounting interest and development within Biopharma across the globe.
The project focused on two representative members of CRLs: 1) the von Hippel-Lindau protein (VHL), which forms part of a Cullin 2 ligase complex; and 2) the suppressor of cytokine signalling 2 (SOCS2) protein, which is a component of a Cullin 5 ligase complex. The P.I. and his team deployed innovative chemistry approaches to target these complexes. Their findings have demonstrated that it is possible to identify small molecules that bind to multiple binding sites and protein-protein interfaces on these proteins. Structural and biophysical elucidation of key non-covalent interactions guided the elaboration of the first series of small molecules targeting the VHL and SOCS2 E3 ligases as useful chemical tools to modulate the interactions and consequently study the biological function of these important E3 ligases. In particular, the work on VHL has led to the development of potent and selective inhibitors series of the interaction of VHL with targets such as HIF1alpha, resulting in HIF1alpha being acutely stabilised inside cells, an outcome of important pharmacological consequences. The P.I. has taken this system one step further and helped to pioneer the “PROTAC” approach, in which bifunctional ligands are created of the VHL ligand conjugated to another moiety that targets a cellular protein, thereby labelling that protein for degradation. The P.I. laboratory has made significant contributions in this area, including elucidating unprecedented structural and mechanical insights into the molecular recognition and mechanism of action of PROTAC molecules, and providing proof-of-concept of inducing an E3 ligase to self-destroy itself via chemically-induced dimerization (which they called homo-PROTAC).
In summary, the discoveries of this ERC grant have demonstrated that CRLs can be targeted successfully to yield cell-active chemical probes. Importantly, this research ushered a revolutionary new approach to modern drug discovery that is to target specific proteins for degradation, for example unwanted disease-realted proteins. This approach is transforming conventional small-molecule drug discovery and is seeing mounting interest and development within Biopharma across the globe.