Potential safety implications of fatty acid-binding protein inhibition.

Fatty acid-binding proteins (FABPs) are small intracellular proteins that regulate fatty acid metabolism, transport, and signalling. There are ten known human isoforms, many of which are upregulated and involved in clinical pathologies. As such, FABP inhibition may be beneficial in disease states such as cancer, and those involving the cardiovascular system, metabolism, immunity, and cognition. Recently, a potent, selective FABP5 inhibitor (ART26.12), with 90-fold selectivity to FABP3 and 20-fold selectivity to FABP7, was found to be remarkably benign, with a no-observed-adverse-effect level of 1000 mg/kg in rats and dogs, showing no genotoxicity, cardiovascular, central, or respiratory toxicity. To understand the potential implication of FABP inhibition more fully, this review systematically assessed literature investigating genetic knockout, knockdown, and pharmacological inhibition of FABP3, FABP4, FABP5, or FABP7. Analysis of the literature revealed that animals bred not to express FABPs showed the most biological effects, suggesting key roles of these proteins during development. FABP ablation sometimes exacerbated symptoms of disease models, particularly those linked to metabolism, inflammatory and immune responses, cardiac contractility, neurogenesis, and cognition. However, FABP inhibition (genetic silencing or pharmacological) had a positive effect in many more disease conditions. Several polymorphisms of each FABP gene have also been linked to pathological conditions, but it was unclear how several polymorphisms affected protein function. Overall, analysis of the literature to date suggests that pharmacological inhibition of FABPs in adults is of low risk.

The emerging role of fatty acid binding protein 7 (FABP7) in cancers.

Fatty acid binding protein 7 (FABP7) is an intracellular protein involved in the uptake, transportation, metabolism, and storage of fatty acids (FAs). FABP7 is upregulated up to 20-fold in multiple cancers, usually correlated with poor prognosis. FABP7 silencing or pharmacological inhibition suggest FABP7 promotes cell growth, migration, invasion, colony and spheroid formation/increased size, lipid uptake, and lipid droplet formation. Xenograft studies show that suppression of FABP7 inhibits tumour formation and tumour growth, and improves host survival. The molecular mechanisms involve promotion of FA uptake, lipid droplets, signalling [focal adhesion kinase (FAK), proto-oncogene tyrosine-protein kinase Src (Src), mitogen-activated protein kinase kinase/p-extracellular signal-regulated kinase (MEK/ERK), and Wnt/ß-catenin], hypoxia-inducible factor 1-alpha (Hif1α), vascular endothelial growth factor A/prolyl 4-hydroxylase subunit alpha-1 (VEGFA/P4HA1), snail family zinc finger 1 (Snail1), and twist-related protein 1 (Twist1). The oncogenic capacity of FABP7 makes it a promising pharmacological target for future cancer treatments.

Discovery and Preclinical Evaluation of a Novel Inhibitor of FABP5, ART26.12, Effective in Oxaliplatin-Induced Peripheral Neuropathy.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity characterised by mechanical allodynia and thermal hyperalgesia, without any licensed medications. ART26.12 is a fatty acid-binding protein (FABP) 5 inhibitor with antinociceptive properties, characterised here for the prevention and treatment of OIPN. ART26.12 binds selectively to FABP5 compared to FABP3, FABP4, and FABP7, with minimal off-target liabilities, high oral bioavailability, and a NOAEL of 1,000 mg/kg/day in rats and dogs. In an established preclinical OIPN model, acute oral dosing (25-100 mg/kg) showed a cannabinoid receptor type 1 (CB1)-dependent anti-allodynic effect lasting up to 8 hours (persisting longer than plasma exposure to ART26.12). Antagonists of cannabinoid receptor type 2 (CB2), peroxisome proliferator-activated receptor alpha, and transient receptor potential cation channel subfamily V member 1 (TRPV1) may have also been implicated. Twice daily oral dosing (25 mg/kg bis in die (BID) for 7 days) showed anti-allodynic effects in an established OIPN model without the development of tolerance. In a prevention paradigm, coadministration of ART26.12 (10 and 25 mg/kg BID for 15 days) with oxaliplatin prevented thermal hyperalgesia, mitigated mechanical allodynia, and attenuated OXA-induced weight loss. Multi-scale analyses revealed widespread lipid modulation, particularly among N-acyl amino acids in the spinal cord, including potential analgesic mediators. Additionally, ART26.12 administration led to upregulation of ion channels in the periaqueductal grey, and broad translational upregulation within the plasma proteome. These results show promise that ART26.12 is a safe and well-tolerated candidate for the treatment and prevention of OIPN through lipid modulation. PERSPECTIVE: Inhibition of fatty acid-binding protein 5 (FABP5) is a novel target for reducing pain associated with chemotherapy. ART26.12 is a safe and well-tolerated small molecule FABP5 inhibitor effective at preventing and reducing pain induced with oxaliplatin through lipid modulation and activation of cannabinoid receptors.

The emerging role of fatty acid binding protein 5 (FABP5) in cancers.

Fatty acid binding protein 5 (FABP5, or epidermal FABP) is an intracellular chaperone of fatty acid molecules that regulates lipid metabolism and cell growth. In patient-derived tumours, FABP5 expression is increased up to tenfold, often co-expressed with other cancer-related proteins. High tumoral FABP5 expression is associated with poor prognosis. FABP5 activates transcription factors (TFs) leading to increased expression of proteins involved in tumorigenesis. Genetic and pharmacological preclinical studies show that inhibiting FABP5 reduces protumoral markers, whereas elevation of FABP5 promotes tumour growth and spread. Thus, FABP5 might be a valid target for novel therapeutics. The evidence base is currently strongest for liver, prostate, breast, and brain cancers, and squamous cell carcinoma (SCC), which could represent relevant patient populations for any drug discovery programme.