Design and characteristics of cytotoxic fibroblast growth factor 1 conjugate for fibroblast growth factor receptor-targeted cancer therapy.

Abstract

Fibroblast growth factor receptors (FGFRs) are attractive candidate cancer therapy targets as they are overexpressed in multiple types of tumors, such as breast, prostate, bladder, and lung cancer. In this study, a natural ligand of FGFR, an engineered variant of fibroblast growth factor 1 (FGF1V), was conjugated to a potent cytotoxic drug, monomethyl auristatin E (MMAE), and used as a targeting agent for cancer cells overexpressing FGFRs, similar to antibodies in antibody-drug conjugates. The FGF1V-valine-citrulline-MMAE conjugate showed a favorable stability profile, bound FGFRs on the cell surface specifically, and efficiently released the drug (MMAE) upon cleavage by the lysosomal protease cathepsin B. Importantly, the conjugate showed a prominent cytotoxic effect toward cell lines expressing FGFR. FGF1V-vcMMAE was highly cytotoxic at concentrations even an order of magnitude lower than those found for free MMAE. This effect was FGFR-specific as cells lacking FGFR did not show any increased mortality.

• Authors: Anna Szlachcic, Malgorzata Zakrzewska, Michal Lobocki, Piotr Jakimowicz, Jacek Otlewski
• Journal: Drug design, development and therapy (Drug Des Devel Ther) Vol. 10 Pg. 2547-60 ( 2016) ISSN: 1177-8881 [Electronic] New Zealand
• PMID: 27563235 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Oligopeptides
• Receptors, Fibroblast Growth Factor
• Recombinant Proteins
• Fibroblast Growth Factor 1
• monomethyl auristatin E

Topics

• Animals
• Antineoplastic Agents (chemistry, therapeutic use)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Drug Design
• Fibroblast Growth Factor 1 (chemistry, metabolism, therapeutic use)
• Humans
• Mice
• Models, Molecular
• Molecular Structure
• NIH 3T3 Cells
• Neoplasms (drug therapy, metabolism, pathology)
• Oligopeptides (chemistry, therapeutic use)
• Receptors, Fibroblast Growth Factor (antagonists & inhibitors, metabolism)
• Recombinant Proteins (metabolism)
• Structure-Activity Relationship