Abstract: Significant progress has been made in the past decade in drugging proteins long considered undruggable using induced proximity approaches that take advantage of the ubiquitin protein homeostasis machinery, including molecular glue degraders and heterobifunctional degraders. While these approaches hold great promise for unmet medical needs, many proteins remain undruggable, particularly those with a high degree of intrinsic protein disorder and thus lacking the ligandable site required for these approaches.
A solution to this challenge is provided by the 14-3-3 family of phosphoprotein regulatory adaptor proteins that recognize and regulate the fate of several thousand disease-driving proteins with intrinsic protein disorder, creating an ordered druggable surface at the interface between client protein and 14-3-3. Small molecule molecular glues take advantage of this ordered interface to stabilize the interaction and enhance the natural regulatory consequences of client protein binding to 14-3-3. These are client-specific and include inhibitory effects such as restraining nuclear entry, inhibiting conformational changes and protein interactions; and activating effects such as stabilizing or enhancing activity.
Proof of concept for drugging this interaction is provided by the natural product fusicoccin, derived from a plant pathogen, and which stabilizes the interaction between 14-3-3 and multiple plant and animal proteins including those of disease relevance such as the oncogene estrogen receptor alpha (ER), restraining ER in the cytoplasm and thus inhibiting its oncogenic transcriptional activity.
At Ambagon Therapeutics we are developing molecular glues stabilizing the interaction between 14-3-3 proteins and disease driving client proteins in cancer and neurodegenerative diseases; these are high value drug targets that are highly disordered and undruggable by other approaches. To enable the discovery of these molecular glues we have built a platform of discovery tools including the 14-3-3 interactome, a database of client proteins across cell lineages discovered by 14-3-3 immunoprecipitation and mass spectroscopy analysis, and the Ambagon library of chemical material enriched for stabilization In addition our drug discovery relies on a modular system of high resolution crystallography characterizing the interfaces between 14-3-3 and the binding sites of hundreds of client proteins and supporting rapid structure based drug design.
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