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|Ref Type||Journal Article|
|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.|
|Date||2021 Aug 09|
|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.|
|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|