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

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...

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Autores principales:	Marialuisa Moccia, Donglin Yang, Naga Rajiv Lakkaniga, Brendan Frett, Nicholas McConnell, Lingtian Zhang, Annalisa Brescia, Giorgia Federico, Lingzhi Zhang, Paolo Salerno, Massimo Santoro, Hong-yu Li, Francesca Carlomagno
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/eab71864d5a542ee8748ff9464f7f61c
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spelling	oai:doaj.org-article:eab71864d5a542ee8748ff9464f7f61c2021-12-02T18:50:44ZTargeted activity of the small molecule kinase inhibitor Pz-1 towards RET and TRK kinases10.1038/s41598-021-95612-42045-2322https://doaj.org/article/eab71864d5a542ee8748ff9464f7f61c2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95612-4https://doaj.org/toc/2045-2322Abstract 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.Marialuisa MocciaDonglin YangNaga Rajiv LakkanigaBrendan FrettNicholas McConnellLingtian ZhangAnnalisa BresciaGiorgia FedericoLingzhi ZhangPaolo SalernoMassimo SantoroHong-yu LiFrancesca CarlomagnoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marialuisa Moccia Donglin Yang Naga Rajiv Lakkaniga Brendan Frett Nicholas McConnell Lingtian Zhang Annalisa Brescia Giorgia Federico Lingzhi Zhang Paolo Salerno Massimo Santoro Hong-yu Li Francesca Carlomagno Targeted activity of the small molecule kinase inhibitor Pz-1 towards RET and TRK kinases
description	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.
format	article
author	Marialuisa Moccia Donglin Yang Naga Rajiv Lakkaniga Brendan Frett Nicholas McConnell Lingtian Zhang Annalisa Brescia Giorgia Federico Lingzhi Zhang Paolo Salerno Massimo Santoro Hong-yu Li Francesca Carlomagno
author_facet	Marialuisa Moccia Donglin Yang Naga Rajiv Lakkaniga Brendan Frett Nicholas McConnell Lingtian Zhang Annalisa Brescia Giorgia Federico Lingzhi Zhang Paolo Salerno Massimo Santoro Hong-yu Li Francesca Carlomagno
author_sort	Marialuisa Moccia
title	Targeted activity of the small molecule kinase inhibitor Pz-1 towards RET and TRK kinases
title_short	Targeted activity of the small molecule kinase inhibitor Pz-1 towards RET and TRK kinases
title_full	Targeted activity of the small molecule kinase inhibitor Pz-1 towards RET and TRK kinases
title_fullStr	Targeted activity of the small molecule kinase inhibitor Pz-1 towards RET and TRK kinases
title_full_unstemmed	Targeted activity of the small molecule kinase inhibitor Pz-1 towards RET and TRK kinases
title_sort	targeted activity of the small molecule kinase inhibitor pz-1 towards ret and trk kinases
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/eab71864d5a542ee8748ff9464f7f61c
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Targeted activity of the small molecule kinase inhibitor Pz-1 towards RET and TRK kinases

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