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Ref Type Journal Article
PMID (28978721)
Authors Venetsanakos E, Brameld KA, Phan VT, Verner E, Owens TD, Xing Y, Tam D, LaStant J, Leung K, Karr DE, Hill RJ, Gerritsen ME, Goldstein DM, Funk JO, Bradshaw JM
Title The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug Clearance.
URL
Abstract Text An increasing number of cancers are known to harbor mutations, translocations, or amplifications in the fibroblast growth factor receptor (FGFR) family of kinases. The FGFR inhibitors evaluated in clinical trials to date have shown promise at treating these cancers. Here, we describe PRN1371, an irreversible covalent inhibitor of FGFR1-4 targeting a cysteine within the kinase active site. PRN1371 demonstrated strong FGFR potency and excellent kinome-wide selectivity in a number of biochemical and cellular assays, including in various cancer cell lines exhibiting FGFR alterations. Furthermore, PRN1371 maintained FGFR inhibition in vivo, not only when circulating drug levels were high but also after the drug had been cleared from circulation, indicating the possibility of sustained FGFR inhibition in the clinic without the need for continuous drug exposure. Durable tumor regression was also obtained in multiple tumor xenografts and patient-derived tumor xenograft models and was sustained even using an intermittent dosing strategy that provided drug holidays. PRN1371 is currently under clinical investigation for treatment of patients with solid tumors. Mol Cancer Ther; 16(12); 2668-76. ©2017 AACR.

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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
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 over exp Advanced Solid Tumor sensitive PRN1371 Preclinical - Cell culture Actionable In a preclinical study, PRN1371 inhibited proliferation in transformed cells overexpressing wild-type FGFR3 in culture (PMID: 28978721). 28978721
FGFR1 over exp Advanced Solid Tumor sensitive PRN1371 Preclinical - Cell culture Actionable In a preclinical study, PRN1371 inhibited proliferation of transformed cells over expressing wild-type FGFR1 in culture (PMID: 28978721). 28978721
FGFR2 N550K Advanced Solid Tumor sensitive PRN1371 Preclinical - Cell culture Actionable In a preclinical study, PRN1371 inhibited proliferation of transformed cells over expressing FGFR2 N550K in culture (PMID: 28978721). 28978721
FGFR3 amp lung non-small cell carcinoma sensitive PRN1371 Preclinical - Pdx Actionable In a preclinical study, PRN1371 treatment resulted in 28.2% tumor growth inhibition in patient-derived xenograft models of FGFR3-amplified non-small cell lung cancer (PMID: 28978721). 28978721
FGFR1 amp lung adenocarcinoma sensitive PRN1371 Preclinical - Pdx Actionable In a preclinical study, PRN1371 treatment resulted in 64.6% tumor growth inhibition in patient-derived xenograft models of FGFR1-amplified lung adenocarcinoma (PMID: 28978721). 28978721
FGFR2 amp lung non-small cell carcinoma sensitive PRN1371 Preclinical - Pdx Actionable In a preclinical study, PRN1371 treatment resulted in 67.5% tumor growth inhibition in patient-derived xenograft models of FGFR2-amplified non-small cell lung cancer (PMID: 28978721). 28978721
FGFR1 V561M Advanced Solid Tumor sensitive PRN1371 Preclinical - Cell culture Actionable In a preclinical study, PRN1371 inhibited proliferation of transformed cells over expressing FGFR1 V561M in culture (PMID: 28978721). 28978721
FGFR3 K650M Advanced Solid Tumor sensitive PRN1371 Preclinical - Cell culture Actionable In a preclinical study, PRN1371 inhibited proliferation of transformed cells over expressing FGFR3 K650M in culture (PMID: 28978721). 28978721
FGFR2 N549K endometrial adenocarcinoma sensitive PRN1371 Preclinical - Cell culture Actionable In a preclinical study, PRN1371 inhibited proliferation of endometrial adenocarcinoma cells harboring FGFR2 N549K in culture (PMID: 28978721). 28978721
FGFR1 amp lung non-small cell carcinoma sensitive PRN1371 Preclinical - Pdx Actionable In a preclinical study, PRN1371 treatment resulted in 96.1% tumor growth inhibition in patient-derived xenograft models of FGFR1-amplified non-small cell lung cancer (PMID: 28978721). 28978721
FGFR2 K660N Advanced Solid Tumor sensitive PRN1371 Preclinical - Cell culture Actionable In a preclinical study, PRN1371 inhibited proliferation of transformed cells over expressing FGFR2 K660N in culture (PMID: 28978721). 28978721 detail...
FGFR2 amp stomach carcinoma sensitive PRN1371 Preclinical - Cell line xenograft Actionable In a preclinical study, PRN1371 inhibited proliferation of FGFR2 amplified gastric carcinoma cells in culture and tumor growth in cell line xenograft models (PMID: 28978721). 28978721
FGFR2 over exp Advanced Solid Tumor sensitive PRN1371 Preclinical - Cell culture Actionable In a preclinical study, PRN1371 inhibited proliferation of transformed cells over expressing wild-type FGFR2 in culture (PMID: 28978721). 28978721
FGFR2 K660E Advanced Solid Tumor sensitive PRN1371 Preclinical - Cell culture Actionable In a preclinical study, PRN1371 inhibited proliferation of transformed cells over expressing FGFR2 K660E in culture (PMID: 28978721). 28978721 detail...