Arylpiperazines as fatty acid transport protein 1 (FATP1) inhibitors with improved potency and pharmacokinetic properties

Matsufuji, Tetsuyoshi; Ikeda, Mika; Naito, Asuka; Hirouchi, Masakazu; Kanda, Shoichi; Izumi, Masanori; Harada, Jun; Shinozuka, Tsuyoshi

doi:10.1016/j.bmcl.2013.02.116

Cited by 17 publications

(20 citation statements)

References 12 publications

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“…Indeed, although FASN inhibitors have shown promising antineoplastic effects in many experimental tumor models, the same drugs might be ineffective against ICC, at least when used alone. Of note, it has been shown that FA uptake is an inherently druggable process, and inhibitors have been described for SLC27A1 . Based on the preliminary data from the present study, it is conceivable that inhibitors of FA uptake, either alone or in association with FASN inhibitors, might be beneficial for the treatment of human ICC.…”

Section: Discussionmentioning

confidence: 65%

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Differential requirement for de novo lipogenesis in cholangiocarcinoma and hepatocellular carcinoma of mice and humans

Che

Tharp

et al. 2016

Hepatology

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Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most prevalent types of primary liver cancer. These malignancies have limited treatment options resulting in poor patient outcomes. Metabolism reprogramming, including increased de novo lipogenesis, is one of the hallmarks of cancer. Fatty Acid Synthase (FASN) catalyzes the de novo synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA. Increased FASN expression has been reported in multiple tumor types, and inhibition of FASN expression has been shown to have tumor-suppressing activity. Intriguingly, we found that while FASN is upregulated in human HCC samples, its expression is frequently low in human ICC specimens. Similar results were observed in mouse ICC models induced by different oncogenes. Ablating FASN in the mouse liver did not affect activated AKT and Notch (AKT/NICD) induced ICC formation in vivo. Furthermore, while both HCC and ICC lesions develop in mice following hydrodynamic injection of AKT and NRas oncogenes (AKT/Ras), deletion of FASN in AKT/Ras mice triggered the development almost exclusively of ICCs. In the absence of FASN, ICC cells might receive lipids for membrane synthesis through exogenous fatty acid uptake. In accordance with the latter hypothesis, ICC cells displayed high expression of fatty acid uptake related proteins and robust long-chain fatty acid uptake. Conclusion, our data demonstrate that FASN dependence is not a universal feature of liver tumors: while HCC development is highly dependent of FASN and its mediated lipogenesis, ICC tumorigenesis can be insensitive to FASN deprivation. Our study supports novel therapeutic approaches to treat this pernicious tumor type with the inhibition of exogenous fatty acid uptake.

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Section: Discussionmentioning

confidence: 65%

“…Of note, it has been shown that FA uptake is an inherently druggable process, and inhibitors have been described for SLC27A1. (46) Based on the preliminary data from the present study, it is conceivable that inhibitors of FA uptake, either alone or in association with FASN inhibitors, might be beneficial for the treatment of human ICC.…”

Section: Discussionmentioning

confidence: 77%

Differential requirement for de novo lipogenesis in cholangiocarcinoma and hepatocellular carcinoma of mice and humans

Che

Tharp

et al. 2016

Hepatology

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“…It is worth speculating that Lipofermata may be used as a partner with Xenical, which will further inhibit free fatty acid transport across the intestinal epithelium. As reviewed above, selected FATP1 and FATP4 inhibitors do not prevent fatty acid absorption 96, 97 .…”

Section: Lipofermatamentioning

confidence: 99%

“…FATP1 and FATP4 have been used to select inhibitors by high through put screening 96, 97 . In each screen, acyl CoA synthetase activity was targeted and not fatty acid transport directly.…”

Section: Fatp/scl27 Family Members As Drug Targetsmentioning

confidence: 99%

“…However, from our work in yeast, the activation and transport activities are separable 36, 59, 61 . FATP1 was particularly chosen as a therapeutic target for the treatment of insulin resistance and various arylpiperazines were selected as inhibitors 96 . However, upon testing in mice, the selected compound imidazolepyridine, did not limit the accumulation of triglyceride in muscle when mice were fed a high fat diet leading to the conclusion that inhibition of FATP1 alone is insufficient to block fatty acid transport 96 .…”

Section: Fatp/scl27 Family Members As Drug Targetsmentioning

confidence: 99%

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Fatty acid transport proteins: targeting FATP2 as a gatekeeper involved in the transport of exogenous fatty acids

et al. 2016

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Summary The fatty acid transport proteins (FATP) are classified as members of the Solute Carrier 27 (Slc27) family of proteins based on their ability to function in the transport of exogenous fatty acids. These proteins, when localized to the plasma membrane or at intracellular membrane junctions with the endoplasmic reticulum, function as a gate in the regulated transport of fatty acids and thus represent a therapeutic target to delimit the acquisition of fatty acids that contribute to disease as in the case of fatty acid overload. To date, FATP1, FATP2, and FATP4 have been used as targets in the selection of small molecule inhibitors with the goal of treating insulin resistance and attenuating dietary absorption of fatty acids. Several studies targeting FATP1 and FATP4 were based on the intrinsic acyl CoA synthetase activity of these proteins and not on transport directly. While several classes of compounds were identified as potential inhibitors of fatty acid transport, in vivo studies using a mouse model failed to provide evidence these compounds were effective in blocking or attenuating fatty acid transport. Studies targeting FATP2 employed a naturally occurring splice variant, FATP2b, which lacks intrinsic acyl CoA synthetase due to the deletion of exon 3, yet is fully functional in fatty acid transport. These studies identified two compounds, 5′-bromo-5-phenyl-spiro[3H-1,3,4-thiadiazole-2,3′-indoline]-2′-one), now referred to as Lipofermata, and 2-benzyl-3-(4-chlorophenyl)-5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one, now called Grassofermata, that are effective fatty acid transport inhibitors both in vitro using a series of model cell lines and in vivo using a mouse model.

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An Overview on Biological Activities of Oxazole, Isoxazoles and 1,2,4-Oxadiazoles Derivatives

Gujjarappa

Sravani

Kabi

et al. 2022

Materials Horizons: From Nature to Nanomaterials

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Arylpiperazines as fatty acid transport protein 1 (FATP1) inhibitors with improved potency and pharmacokinetic properties

Cited by 17 publications

References 12 publications

Differential requirement for de novo lipogenesis in cholangiocarcinoma and hepatocellular carcinoma of mice and humans

Differential requirement for de novo lipogenesis in cholangiocarcinoma and hepatocellular carcinoma of mice and humans

Fatty acid transport proteins: targeting FATP2 as a gatekeeper involved in the transport of exogenous fatty acids

An Overview on Biological Activities of Oxazole, Isoxazoles and 1,2,4-Oxadiazoles Derivatives

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