Chemical inhibition of prometastatic lysyl-tRNA synthetase–laminin receptor interaction

Beyond its canonical role in translation, lysyl-tRNA synthetase (KRS) stabilizes the prometastatic 67-kDa laminin receptor (67LR) in the plasma membrane. A small-molecule inhibitor of the KRS-67LR interaction modulates the KRS-promoted metastatic potential of 67LR without disrupting the normal function of each protein. Lysyl-tRNA synthetase (KRS), a protein synthesis enzyme in the cytosol, relocates to the plasma membrane after a laminin signal and stabilizes a 67-kDa laminin receptor (67LR) that is implicated in cancer metastasis; however, its potential as an antimetastatic therapeutic target has not been explored. We found that the small compound BC-K-YH16899, which binds KRS, impinged on the interaction of KRS with 67LR and suppressed metastasis in three different mouse models. The compound inhibited the KRS-67LR interaction in two ways. First, it directly blocked the association between KRS and 67LR. Second, it suppressed the dynamic movement of the N-terminal extension of KRS and reduced membrane localization of KRS. However, it did not affect the catalytic activity of KRS. Our results suggest that specific modulation of a cancer-related KRS-67LR interaction may offer a way to control metastasis while avoiding the toxicities associated with inhibition of the normal functions of KRS.