BCL2A1 inhibitors target diabetes, inflammation
Many pathogenic cell states (e.g., tumor cells or activated immune cells) depend on anti-apoptotic proteins for their survival, which makes these proteins effective therapeutic targets, as evidenced by the success in pharmacologic targeting of Bcl-2. Bcl2A1 is one such survival factor induced by inflammation in a variety of cell types, including cancer cells, B and T cells, neutrophils, and mast cells. Thus, there is potential that targeting Bcl2A1 could be developed as a strategy against a wide variety of diseases. In particular, our data suggest that Bcl2A1 is a significant survival factor in (i) diabetogenic CD4+ T cells that drive type I diabetes (T1D); (ii) neutrophil survival during inflammation, particularly during pre-term birth. Therefore, we have begun screening molecular libraries for compounds that inhibit Bcl2A1 function. We have developed a few first generation compounds that appear promising in our in vitro screens that we will further develop in preparation for testing in pre-clinical animal models.
- Conditions with persistent neutrophilic inflammation (eg. pre-term birth), CD4+ T cell driven autoimmunity (eg type I diabetes, T1D), and mast cell mediated disease (eg. allergy).
- In-vitro and in-vivo models, including mouse models of T1D, pre-term birth, and mice deficient in Bcl2A1.
- Identified twelve promising higher-affinity inhibitory compounds that are being tested in a cellular apoptosis assay.