Tartrate-resistant acid phosphatase (TRAP/ACP5/
uteroferrin/
purple acid phosphatase/
PP5) has received considerable attention as a newly discovered proinvasion
metastasis driver associated with different
malignancies. This renders TRAP an interesting target for novel anti-
cancer therapy approaches. TRAP exists as two
isoforms, 5a and 5b, where the 5a
isoform represents an enzymatically less active monomeric precursor to the more enzymatically active 5b
isoform generated by proteolytic excision of a repressive loop domain. Recently, three novel lead compounds were identified by fragment-based screening and demonstrated to be efficient TRAP
enzyme inhibitors in vitro. We conclude that one of the three compounds i.e. 5-phenylnicotinic
acid (CD13) was efficient as a TRAP inhibitor with Kic values in the low micromolar range towards the TRAP 5b
isoform, but was not able to inhibit the TRAP 5a
isoform. Structure-based docking revealed similar interactions of CD13 with the active site in both TRAP
isoforms. In stably TRAP-overexpressing MDA-MB-231
breast cancer cells, CD13 inhibited intracellular TRAP activity and showed no cytotoxicity at 200 µM. Furthermore, CD13 selectively blocked the TRAP 5b
isoform compared to the TRAP 5a in cultured cells, indicating the usefulness of CD13 for assessing the different
biological functions of the two TRAP
isoforms 5a and 5b in cell systems. Moreover, inhibition of cell migration and invasion of stably TRAP-overexpressing MDA-MB-231 by CD13 was observed. These data establish a proof of principle that a small chemical inhibitor of the TRAP
enzyme can block TRAP-dependent functions in
cancer cells.