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Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
Published on: September 30, 2019
The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR
Eleni Venetsanakos1, Ken A Brameld1, Vernon T Phan1
1Principia Biopharma, South San Francisco, California.
Abstract:
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.
Insights
A new drug, PRN1371, shows promise in treating cancers with fibroblast growth factor receptor (FGFR) alterations. This irreversible FGFR inhibitor demonstrated sustained efficacy and durable tumor regression in preclinical models, suggesting potential for intermittent dosing in patients.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Aberrant fibroblast growth factor receptor (FGFR) signaling, through mutations, translocations, or amplifications, is implicated in various cancers.
- Existing FGFR inhibitors have shown therapeutic potential in clinical trials for FGFR-driven malignancies.
Purpose of the Study:
- To characterize PRN1371, a novel irreversible covalent inhibitor targeting FGFR1-4.
- To evaluate the preclinical efficacy and pharmacokinetic profile of PRN1371 in cancer models with FGFR alterations.
Main Methods:
- Biochemical and cellular assays were used to assess PRN1371's potency and kinome-wide selectivity against FGFR kinases.
- In vivo studies in tumor xenografts and patient-derived xenografts evaluated PRN1371's efficacy, pharmacokinetic properties, and dosing strategies.
Main Results:
- PRN1371 exhibited potent FGFR inhibition and high selectivity across various cancer cell lines with FGFR alterations.
- Sustained FGFR inhibition was observed in vivo, even after drug clearance, suggesting potential for non-continuous dosing.
- PRN1371 demonstrated durable tumor regression in multiple preclinical models, including with intermittent dosing schedules.
Conclusions:
- PRN1371 is a potent and selective irreversible FGFR inhibitor with promising preclinical anti-tumor activity.
- The drug's pharmacokinetic profile supports sustained target engagement and intermittent dosing strategies.
- PRN1371 is currently under clinical investigation for solid tumors harboring FGFR alterations.
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