Targeting Mesotrypsin in Breast, Prostate, Pancreatic and Lung Cancers
Optimization of two amino acids (green) of the natural trypsin inhibitor BPTI (gray ribbon, top) produced an improved inhibitor with structural complementarity to mesotrypsin (beige).
Mesotrypsin, encoded by the PRSS3 gene, is a human serine protease whose upregulation has been implicated in promoting tumor progression. Mesotrypsin inhibitors could offer valuable tools for deciphering the pathological role of this enzyme and could also form the basis for novel therapeutic strategies targeting mesotrypsin.
Dr. Radisky's Proteases in Cancer Laboratory is developing mesotrypsin inhibitors and evaluating their therapeutic potential in preclinical models of breast cancer, pancreatic cancer, prostate cancer and lung cancer.
Mesotrypsin inhibitors could offer a new approach to slowing cancer cell malignant growth, invasion and metastasis.
But targeting mesotrypsin specifically is a challenge because mesotrypsin is one enzyme among a large family of proteases with similar structure and specificity. In addition, mesotrypsin has proved notoriously resistant to inhibition by many inhibitors of other trypsins.
By using site-directed mutagenesis, biochemical assays and X-ray crystallography to define features of mesotrypsin specificity that are distinct from other serine proteases, Dr. Radisky and her team in the Proteases in Cancer Laboratory created a prototype mesotrypsin inhibitor with stronger affinity than any previous natural or artificial inhibitor. This engineered inhibitor showed striking anti-cancer activity in physiologically relevant assays of breast cancer cell malignant growth, pancreatic cancer cell invasion and prostate cancer cell invasion.
Through a partnership with the protein engineering laboratory of Niv Papo at Ben-Gurion University of the Negev in Israel, Dr. Radisky's lab has used directed evolution approaches to screen large libraries of protein inhibitors based on a natural human protease inhibitor, APPI. This collaborative work has identified even more potent mesotrypsin inhibitors.
In other studies, Dr. Radisky's team has used in silico docking screens or, alternatively, high-throughput screening of large compound libraries to identify novel small-molecule inhibitors of mesotrypsin.
Further development of these polypeptide and small-molecule inhibitors for enhanced mesotrypsin selectivity may generate targeted therapeutics capable of suppressing cancer progression in patients.
Dr. Radisky has published numerous scientific articles about her research on targeting mesotrypsin in cancer, including: