Objective
The overall objective of this proposal is to develop small molecule compounds that result in the targeted protein degradation of the alpha cell specific transcription factor ARX. We will combine a rational design approach for designing DNA-based degraders with a screening approach for discovering pharmacologically preferable molecular glue compounds.
Background Rationale
Loss of ARX has been shown to induce the conversion of glucagon-producing alpha cells to beta-like cells that can alleviate disease phenotypes in Type 1 diabetes models. However, currently no small molecules are available that can inhibit ARX. The new pharmacology of targeted protein degradation for the first time makes attempting to obtain such compounds feasible.
Description of Project
In type 1 diabetes, the insulin-producing beta cells in the islets of Langerhans are being destroyed by an autoimmune reaction. Inducing insulin expression in other non-beta cells is a key objective of regenerative medicine approaches aiming at developing a cure of type 1 diabetes. Pancreatic alpha cells, that also reside in the islets of Langerhans, have long been proposed as an endogenous cell source for the regeneration of beta cell mass. However clinical translation of currently available approaches has not been achieved so far.
Previous research has shown that so called master regulatory transcription factors are key determinants of cell fate decisions. For glucagon-producing alpha cells, ARX is such a master regulator. In genetic models, loss of ARX in mature alpha cells causes them to transdifferentiate into insulin expressing beta-like cells.
Converting this finding to novel therapies is challenging due to the chemical nature and structure of ARX that precludes classical inhibitor development. However, recent discoveries of compounds acting by novel pharmacological mechanisms have opened up new possibilities. Molecular glues are small molecules that induce the proximity between a target protein and an ubiquitin ligase, thereby earmarking the protein for targeted protein degradation. While the approach has never been applied to ARX, few other transcription factors can be degraded by this mechanism.
We have previously implemented ARX reporter systems and developed methods for the systematic discovery of molecular glue degraders. Here, we propose the high-risk high-reward project to combine the two areas of expertise to attempt to discover first chemical ARX degraders. These compounds have the potential to be further developed into therapeutic agents that might provide a new beta cell source by alpha cell transdifferentiation.
Anticipated Outcome
This is a high risk-high reward project. If successful, it would constitute one of the few examples of successful degradation of a transcription factor. While even in the best possible outcome, compounds emerging from this project after the 1-year funding period will require further medicinal chemistry optimization before preclinical testing, it is anticipated that successful proof of concept will generate lots of excitement and funding possibilities for further development towards the clinic.
Relevance to T1D
In type 1 diabetes, the insulin-producing beta cells in the islets of Langerhans are being destroyed by an autoimmune reaction. Inducing insulin expression in other non-beta cells is a key aim of regenerative medicine towards a cure of type 1 diabetes. Pancreatic alpha cells, that also reside in the islets of Langerhans, have long been proposed as an endogenous cell source for the regeneration of beta cell mass. However clinical translation of currently available approaches has not been achieved so far. ARX is one of the best targets for inducing alpha cell transdifferentiation based on genetic models, however, has not been actionable pharmacologically so far.