Cathepsins are a family of proteases that have been implicated in many diseases.
Virobay compounds are highly potent, orally active and drug-like; addressing common problems in the design of cathepsin inhibitors.
Extracellular proteases are involved in key stages of cancer malignancy including tumor growth, invasion, angiogenesis, and metastasis. Cysteine cathepsins, particularly cathepsin L, B and S, have been implicated in many of these processes. As such, they represent novel targets for small molecule therapeutics in cancer. They contribute to the degradation of the vascular basement membrane and activation and release of pro-angiogenic factors. Cathepsin proteolytic activity is associated with the invasion of cancer cells into surrounding tissue through the disruption of cell-cell junctions and the degradation of basement membrane and matrix components. They are involved in intravasation of cancer cells into circulation at a primary site and extravasation at secondary sites promoting colonization.
Increases in cathepsin expression and activity have been reported in human malignancies. Elevated cathepsin B expression correlates with poor prognosis in multiple cancer types. Cathepsin B and L are progressively upregulated with increasing malignancy in pancreatic cancer, and cathepsin B expression is high in pancreatic lymph node metastases.
Cathepsin S may play a key role in tumor angiogenesis. Cathepsin S inhibition in endothelial cells reduces microvessel formation and endothelial cells from cathepsin S knockout mice have impaired matrigel invasion. Multiple cathepsins are involved in invasive tumor growth and angiogenesis in models of cancer. Cathepsin B, L, and S are upregulated during tumor development and their activity becomes localized to the invasive front of tumors. Broad acting pan cathepsin inhibitors are efficacious in cancer models, reducing tumor invasiveness, vascular branching and angiogenic switching, and tumor cell proliferation.
Virobay has a series of orally bioavailable pan cathepsin inhibitors. We have demonstrated efficacy of VBY-825 in a model of pancreatic cancer. VBY-825 also inhibits tumor angiogenesis and cell invasion in vitro.