Evaluation of FASN inhibitors by a versatile toolkit reveals differences in pharmacology between human and rodent FASN preparations and in antiproliferative efficacy in vitro vs. in situ in human cancer cells

Singha, Prosanta; Mäklin, Kiira; Vihavainen, Taina; Laitinen, Tuomo; Nevalainen, Tapio; Patil, Mahadeo R.; Tonduru, Arun Kumar; Poso, Antti; Laitinen, Jarmo T.; Savinainen, Juha R.

doi:10.1016/j.ejps.2020.105321

Cited by 7 publications

(4 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Owing to poor oral bioavailability and metabolic instability, several reformulation efforts were initiated, including a hydrophilic nanoparticle delivery system 242 , poly(ethylene glycol)-conjugated poly(lactic-co-glycolic acid) nanoparticles 243 and folate receptor-targeted micellar nanoparticles 244 ; however, none of these has moved into clinical development. Fasnall, a thiophenopyrimidine derivative also targets cofactor binding sites in multiple domains and in pharmacokinetic and toxicity studies shows no toxic effects 245 urea-based substitutions to Fasnall, led to the identification of MP-ML-24-N1, which inhibits FAS through the TE domain and has good cellular permeability 246 . Lastly, IPI-9119 irreversibly inhibits the TE domain by promoting acetylation of the catalytic serine residue and has shown high potency and selectivity against FAS as well as good pharmacological properties 247 .…”

Section: Pharmacological Inhibitorsmentioning

confidence: 99%

Lipogenesis inhibitors: therapeutic opportunities and challenges

Batchuluun

Pinkosky

Steinberg

2022

Nat Rev Drug Discov

215

135

View full text Add to dashboard Cite

show abstract

Section: Pharmacological Inhibitorsmentioning

confidence: 99%

Lipogenesis inhibitors: therapeutic opportunities and challenges

Batchuluun

Pinkosky

Steinberg

2022

Nat Rev Drug Discov

215

135

View full text Add to dashboard Cite

show abstract

“…The growth inhibition of LNCaP and PC3 following treatment with FASN inhibitors was carried out according to recently published methods [ 64 ]. Briefly, LNCaP and PC3 cells were seeded at 1 mL/well on 24-well plates at a density of 1 × 10 6 cells/mL or 1.25 × 10 4 cells/mL, respectively.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Evaluation of 11C-Labeled Triazolones as Probes for Imaging Fatty Acid Synthase Expression by Positron Emission Tomography

et al. 2022

View full text Add to dashboard Cite

Cancer cells require lipids to fulfill energetic, proliferative, and signaling requirements. Even though these cells can take up exogenous fatty acids, the majority exhibit a dependency on de novo fatty acid synthesis. Fatty acid synthase (FASN) is the rate-limiting enzyme in this process. Expression and activity of FASN is elevated in multiple cancers, where it correlates with disease progression and poor prognosis. These observations have sparked interest in developing methods of detecting FASN expression in vivo. One promising approach is the imaging of radiolabeled molecular probes targeting FASN by positron emission tomography (PET). However, although [11C]acetate uptake by prostate cancer cells correlates with FASN expression, no FASN-specific PET probes currently exist. Our aim was to synthesize and evaluate a series of small molecule triazolones based on GSK2194069, an FASN inhibitor with IC50 = 7.7 ± 4.1 nM, for PET imaging of FASN expression. These triazolones were labeled with carbon-11 in good yield and excellent radiochemical purity, and binding to FASN-positive LNCaP cells was significantly higher than FASN-negative PC3 cells. Despite these promising characteristics, however, these molecules exhibited poor in vivo pharmacokinetics and were predominantly retained in lymph nodes and the hepatobiliary system. Future studies will seek to identify structural modifications that improve tumor targeting while maintaining the excretion profile of these first-generation 11C-methyltriazolones.

show abstract

“…Inhibitor of the β-ketoacyl reductase (KR) activity of human fatty acid synthase (FAS) Hardwicke et al (2014) Inhibits cell growth in some cancer cells Hardwicke et al (2014), but its effect looks associated with general toxicity in other cell lines Singha et al (2020).…”

Section: Gsk2194069mentioning

confidence: 99%

High-throughput in situ perturbation of metabolite levels in the tumor micro-environment reveals favorable metabolic condition for increased fitness of infiltrated T-cells

Valvo

Parietti

Deans

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Tumor-infiltrating immune cells experience significant metabolic reprogramming in the tumor microenvironment (TME), and they share similar metabolic pathways and nutrient needs with malignant cells. This positions these cell types in direct nutrient competition in the TME. We currently lack a complete understanding of the similarities, differences, and functional consequences of the metabolic pathways utilized by activated immune cells from different lineages versus neoplastic cells. This study applies a novel in situ approach using implantable microdevices to expose the tumor to 27 controlled and localized metabolic perturbations in order to perform a systematic investigation into the metabolic regulation of the cellular fitness and persistence between immune and tumor cells directly within the native TME. Our findings identify the most potent metabolites, notably glutamine and arginine, that induce a favorable metabolic immune response in a mammary carcinoma model, and reveal novel insights on less characterized pathways, such as cysteine and glutathione. We then examine clinical samples from cancer patients to confirm the elevation of these pathways in tumor regions that are enriched in activated T cells. Overall, this work provides the first instance of a highly multiplexed in situ competition assay between malignant and immune cells within tumors using a range of localized microdose metabolic perturbations. The approach and findings may be used to potentiate the effects of T cell stimulating immunotherapies on a tumor-specific or personalized basis through targeted enrichment or depletion of specific metabolites.

show abstract

Evaluation of FASN inhibitors by a versatile toolkit reveals differences in pharmacology between human and rodent FASN preparations and in antiproliferative efficacy in vitro vs. in situ in human cancer cells

Abstract: Evaluation of FASN inhibitors by a versatile toolkit reveals differences in pharmacology between human and rodent FASN preparations and in antiproliferative efficacy in vitro vs. in situ in human cancer cells,

Cited by 7 publications

References 35 publications

Lipogenesis inhibitors: therapeutic opportunities and challenges

Lipogenesis inhibitors: therapeutic opportunities and challenges

Synthesis and Evaluation of 11C-Labeled Triazolones as Probes for Imaging Fatty Acid Synthase Expression by Positron Emission Tomography

High-throughput in situ perturbation of metabolite levels in the tumor micro-environment reveals favorable metabolic condition for increased fitness of infiltrated T-cells

Contact Info

Product

Resources

About