Figure 1.

KLK6 ABP development and applications. Designs for ABPs selective for KLK6 over other KLKs abundant in PDAC (KLK7 and KLK8) were based on the preferred natural and unnatural amino acids associated with each KLK6 subsite (S1–S4) discovered using a combinatorial positional scanning library. On-target activity of an optimized biotinylated ABP (bABP 17, IMP-2352) was analyzed by X-ray crystallography and chemical proteomics; the probe was shown to inhibit PDAC cell invasion and migration and used to identify potential KLK6 substrates mediating this phenotype in PDAC cells in combination with N-terminal proteome analysis (N-terminomics).