Targeted activity of the small molecule kinase inhibitor Pz-1 towards RET and TRK kinases

Sci Rep. 2021 Aug 9;11(1):16103. doi: 10.1038/s41598-021-95612-4.


We have recently described Pz-1, a benzimidazole-based type-2 RET and VEGFR2 inhibitor. Based on a kinome scan, here we show that Pz-1 is also a potent (IC50 < 1 nM) TRKA/B/C inhibitor. Pz-1 potently inhibited proliferation of human cancer cells carrying either RET- or TRKA oncoproteins (IC50 ~ 1 nM), with a negligible effect against RET- and TRKA-negative cells. By testing mutations, known to mediate resistance to other compounds, RET G810R/S, but not L730I/V, E732K, V738A and Y806N, showed some degree of resistance to Pz-1. In the case of TRKA, G595R and F589L, but not G667C, showed some degree of resistance. In xenograft models, orally administered Pz-1 almost completely inhibited RET- and TRKA-mutant tumours at 1-3 mg/kg/day but showed a reduced effect on RET/TRKA-negative cancer models. The activity, albeit reduced, on RET/TRKA-negative tumours may be justified by VEGFR2 inhibition. Tumours induced by NIH3T3 cells transfected by RET G810R and TRKA G595R featured resistance to Pz-1, demonstrating that RET or TRKA inhibition is critical for its anti-tumourigenic effect. In conclusion, Pz-1 represents a new powerful kinase inhibitor with distinct activity towards cancers induced by oncogenic RET and TRKA variants, including some mutants displaying resistance to other drugs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Line
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-ret / metabolism*
  • Receptor, trkA / metabolism*
  • Small Molecule Libraries / pharmacology*


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Receptor, trkA