Abstract
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.
Highlights
We have recently described Pz-1, a benzimidazole-based type-2 RET and VEGFR2 inhibitor
A vast group of neoplasms, including breast, lung and colorectal (CRC) carcinoma, melanoma and leukaemia are positive for TRKs fusions in less than 5% of c ases[4,5,10]
We have recently reported the identification of a novel tyrosine kinase inhibitors (TKIs), named Pz-1, able to potently inhibit RET and VEGFR2 kinases (IC50 < 1 nM)[55]
Summary
We have recently described Pz-1, a benzimidazole-based type-2 RET and VEGFR2 inhibitor. 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. 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. Abbreviations RTK Receptor tyrosine kinase TKI Tyrosine kinase inhibitor PTC Papillary thyroid carcinoma MTC Medullary thyroid carcinoma NSCLC Non-small-cell lung cancer CRC Colorectal cancer PFS Progression free survival TRK Tropomyosin receptor kinase VEGFR2 Vascular endothelial growth factor receptor 2 RET Rearranged during transfection MASC Mammary analogue secretory carcinoma. TRKs overexpression (breast, lung, skin carcinoma)[11], splice variants and in-frame deletions (AML and neuroblastoma)[12,13] have been reported
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