Reference Detail

Ref Type

Journal Article

PMID

(34373541)

Authors

Moccia M, Yang D, Lakkaniga NR, Frett B, McConnell N, Zhang L, Brescia A, Federico G, Zhang L, Salerno P, Santoro M, Li HY, Carlomagno F

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Scientific reports	11	1	2021 Aug 09	16103	Sci Rep

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Pz-1	Pz-1	9	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Pz-1			RET Inhibitor 53 Trk Receptor Inhibitor (Pan) 32 VEGFR2 Inhibitor 37	Pz-1 is a small molecule inhibitor with activity against Ret and Kdr (VEGFR2), as well as NTRK1/2/3, which may result in tumor growth inhibition (PMID: 26126987, PMID: 34373541).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
RET	G810R	missense	unknown	RET G810R lies within the protein kinase domain of the Ret protein (UniProt.org). G810R is associated with RET inhibitor resistance in the context of RET fusions (PMID: 31988000, PMID: 33161056, PMID: 34373541), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jun 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET C634W	medullary thyroid carcinoma	sensitive	Pz-1	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Pz-1 treatment inhibited downstream signaling and cell growth of a medullary thyroid carcinoma cell line harboring RET C634W in culture, and inhibited tumor growth in cell line xenograft models (PMID: 34373541).	34373541
RET M918T	Advanced Solid Tumor	sensitive	Pz-1	Preclinical - Cell culture	Actionable	In a preclinical study, Pz-1 treatment inhibited Ret phosphorylation and growth of transformed cells expressing RET M918T in culture (PMID: 34373541).	34373541
RET M918T	medullary thyroid carcinoma	sensitive	Pz-1	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Pz-1 treatment inhibited downstream signaling and growth of a medullary thyroid carcinoma cell line harboring RET M918T in culture, and inhibited tumor growth in cell line xenograft models (PMID: 34373541).	34373541
RET C634R	Advanced Solid Tumor	sensitive	Pz-1	Preclinical - Cell culture	Actionable	In a preclinical study, Pz-1 treatment inhibited Ret phosphorylation and growth of transformed cells expressing RET C634R in culture (PMID: 34373541).	34373541