ArticlePloS one2013
Rational design of a fibroblast growth factor 21-based clinical candidate, LY2405319.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
89 citing papers in PubMed, 1 synthesis or guideline pooled it, 164 citations in OpenAlex.
- Use of FGF21 analogs for the treatment of metabolic disorders: a systematic review and meta-analysis.Archives of endocrinology and metabolism · 2023Pooled it
- AKR-001, an Fc-FGF21 Analog, Showed Sustained Pharmacodynamic Effects on Insulin Sensitivity and Lipid Metabolism in Type 2 Diabetes Patients.Cell reports. Medicine · 2020Trial
- Structure-function relationship in FGF signaling: rational design of highly stable FGF2 variants and their effect on cell growth, metabolism, and survival.Journal of biological engineering · 2026Article
- FGF family in health and disease.Molecular biomedicine · 2026Review
- Antagonism of β-klotho signaling by peptide 19 impairs wheel running in male mice and potentiates the cisplatin-induced decrease in wheel running.Frontiers in pharmacology · 2026Article
- Type 2 diabetes mellitus - conventional therapies and future perspectives in innovative treatment.Biochemistry and biophysics reports · 2025Review
- FGF-based drug discovery: advances and challenges.Nature reviews. Drug discovery · 2025Review
- Pathology and Therapeutic Significance of Fibroblast Growth Factors.Targets (Basel) · 2025Article
- Research progress on the role of FGF21 in insulin resistance.Frontiers in endocrinology · 2025Review
- Fibroblast Growth Factors: Roles and Emerging Therapeutic Applications.Current drug targets · 2025Review
- Novel FGF21 analogues through structure-based optimization for therapeutic development.Acta biochimica et biophysica Sinica · 2024Article
- Computer-aided engineering of stabilized fibroblast growth factor 21.Computational and structural biotechnology journal · 2024Article
- Housing mice near vs. below thermoneutrality affects drug-induced weight loss but does not improve prediction of efficacy in humans.Cell reports · 2024Article
- Development of Zalfermin, a Long-Acting Proteolytically Stabilized FGF21 Analog.Journal of medicinal chemistry · 2024Article
- Transplantation of committed pre-adipocytes from brown adipose tissue improves whole-body glucose homeostasis.iScience · 2024Article
- Potential role of Akt in the regulation of fibroblast growth factor 21 by berberine.Journal of natural medicines · 2024Article
- Overexpression and Purification of Mitogenic and Metabolic Fibroblast Growth Factors.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Exploring endocrine FGFs - structures, functions and biomedical applications.International journal of biochemistry and molecular biology · 2024Review
- Mechanisms of Fibroblast Growth Factor 21 Adsorption on Macroion Layers: Molecular Dynamics Modeling and Kinetic Measurements.Biomolecules · 2023Article
- Exploring the Structural and Functional Diversity among FGF Signals: A Comparative Study of Human, Mouse, and Xenopus FGF Ligands in Embryonic Development and Cancer Pathogenesis.International journal of molecular sciences · 2023Review
29 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
15 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Fibroblast growth factor 21 is a novel hormonal regulator with the potential to treat a broad variety of metabolic abnormalities, such as type 2 diabetes, obesity, hepatic steatosis, and cardiovascular disease. Human recombinant wild type FGF21 (FGF21) has been shown to ameliorate metabolic disorders in rodents and non-human primates. However, development of FGF21 as a drug is challenging and requires re-engineering of its amino acid sequence to improve protein expression and formulation stability. Here we report the design and characterization of a novel FGF21 variant, LY2405319. To enable the development of a potential drug product with a once-daily dosing profile, in a preserved, multi-use formulation, an additional disulfide bond was introduced in FGF21 through Leu118Cys and Ala134Cys mutations. FGF21 was further optimized by deleting the four N-terminal amino acids, His-Pro-Ile-Pro (HPIP), which was subject to proteolytic cleavage. In addition, to eliminate an O-linked glycosylation site in yeast a Ser167Ala mutation was introduced, thus allowing large-scale, homogenous protein production in Pichia pastoris. Altogether re-engineering of FGF21 led to significant improvements in its biopharmaceutical properties. The impact of these changes was assessed in a panel of in vitro and in vivo assays, which confirmed that biological properties of LY2405319 were essentially identical to FGF21. Specifically, subcutaneous administration of LY2405319 in ob/ob and diet-induced obese (DIO) mice over 7-14 days resulted in a 25-50% lowering of plasma glucose coupled with a 10-30% reduction in body weight. Thus, LY2405319 exhibited all the biopharmaceutical and biological properties required for initiation of a clinical program designed to test the hypothesis that administration of exogenous FGF21 would result in effects on disease-related metabolic parameters in humans.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.