TP-0184 (BMPR Signaling Inhibitor)
Hepcidin is a peptide liver hormone that functions as a master regulator of serum iron levels, particularly in response to inflammation. Hepcidin is transcriptionally regulated by activin-like kinase 2 (ALK2), which is a bone morphogenic protein (BMP) receptor that activates SMAD transcription factors. In chronic inflammatory conditions, ALK2 is constitutively activated due to pro-inflammatory cytokine signaling resulting in high circulating hepcidin levels, low serum iron and anemia.
The anemia associated with chronic diseases, such as rheumatoid arthritis, kidney disease, and even cancer are frequently severe and debilitating. Current treatment approaches are inadequate and center on blood transfusions and erythropoietin (EPO)-based therapeutics. EPO-based therapies fail to target anemia of chronic disease (ACD) at its root cause, which is a hepcidin-driven lack of bioavailable iron. High doses of EPO-based therapies do provide some benefit, but only at a significant cost and risk of potential side-effects. EPO-sparing strategies are therefore greatly needed to complement the use of EPO and to decrease the healthcare industry's dependence on EPO-based therapies.
TP-0184 decreases hepcidin expression through the inhibition of ALK2. It has demonstrated profound preclinical activity in models of anemia driven by acute and chronic inflammation and by cancer. TP-0184 lowers liver and circulating hepcidin levels and increases bioavailable iron levels in the serum. TP-0184 represents a first-in-class ALK2 inhibitor with the potential to be an orally administered small molecule for the treatment of ACD.