Back Cover: α-Ketobenzothiazole Serine Protease Inhibitors of Aberrant HGF/c-MET and MSP/RON Kinase Pathway Signaling in Cancer (ChemMedChem 6/2016)

The back cover picture shows a rationally designed inhibitor (yellow) of HGFA (hepatocyte growth factor activator), matriptase, and hepsin. HGFA, matriptase, and hepsin proteolytically process pro‐HGF and pro‐macrophage stimulating protein (pro‐MSP), to the activating ligands for c‐MET and RON kinases, which are implicated in tumor progression. The inhibitors contain a Kbt (ketobenzothiazole) serine‐trapping warhead as seen in the molecular model of the inhibitor bound to HGFA, matriptase, and hepsin serine proteases (catalytic Asp102, His57, and Ser195 highlighted). Our inhibitors are unique to others, since they contain P3’ substituents in the C‐terminal S3’ pocket, which varies from His in HGFA, to Asp in matriptase, and Asn in hepsin. In the paper, we describe our efforts to develop a chemical toolkit of inhibitors which have good potency and selectivity for either one, two, or all three of HGFA, matriptase, and hepsin. Shown in the bottom right, Kbt inhibitors abrogate the HGF‐mediated scattering of invasive DU145 prostate cancer cells. The inhibitors are promising leads for optimization as new drugs for preventing tumor progression and treating metastatic cancer. More information can be found in the Full Paper by James W. Janetka et al. on page 685 in Issue 6, 2016 (DOI:10.1002/cmdc.201500600).