A new study, recently published on Nature Biotechnology, shows a novel screening platform to identify conformation-locking antibodies for molecular probes (CLAMPS) useful to distinguish and induce rare protein conformational states that could facilitate the study and drugging of dynamic proteins. RAS proteins are major oncogenic drivers of many cancers, but the lack of stable pockets has hindered drug development: thus, the approach has been used for KRAS, showing the it could enable discovering of ligands that could serve as leads for the development of new inhibitors.
Small molecules that stabilize inactive protein conformations are an underutilized strategy for drugging dynamic or otherwise intractable proteins. The inherent conformational flexibility of proteins challenges the discovery of potential small-molecule inhibitors that trap in inactive states some dynamic proteins involved in diseases: small-molecule require high affinity to bind a highly dynamic pocket, thus strategies to detect or even induce a particular protein conformation would provide a new way to elucidate the biological role of these conformations in cells and enable new drug discovery efforts. In this study, researchers created a screening platform to identify CLAMPS that distinguish and induce rare protein conformational states, discovering one CLAMP that enables the visualization of KRAS covalent modification in vivo and that can be used to investigate response heterogeneity to KRAS inhibitors in patient tumors. The platform identified also a second CLAMP that enhances the affinity of weak ligands binding to a specific KRAS region by stabilizing a specific conformation of KRAS.
The discovery of the two KRAS CLAMPs has revealed new insights into KRAS covalent modification and can be used to visualize and track inhibitor-bound KRAS in both cells and in vivo tumor models. The CLAMP platform has led to the discovery of antibodies that recognize conformations existing within the dynamic KRAS switch regions, highlighting the importance of locking conformationally dynamic proteins in different states to enable the discovery of unique conformation-specific antibodies. CLAMPs can also induce and lock a conformation in the absence of ligand, and thus enable small-molecule discovery efforts against transient pockets within conformationally dynamic proteins, thereby enabling the discovery of ligands that could serve as leads for the development of drugs in a high-throughput screen.