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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 Scientific reports
Vol 11
Issue 1
Date 2021 Aug 09
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
Drug Name Trade Name Synonyms Drug Classes Drug Description
Pz-1 RET Inhibitor 44 Trk Receptor Inhibitor (Pan) 26 VEGFR2 Inhibitor 35 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, Apr 2022). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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
RET M918T thyroid gland medullary 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 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 C634W thyroid gland medullary 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