Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	16	12	2017 Dec	2668-2676	Mol Cancer Ther

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
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...
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 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
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 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 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 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...
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
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
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 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
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
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
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