Imidazopyridine-Based Fatty Acid Synthase Inhibitors That Show Anti-HCV Activity and in Vivo Target Modulation

Oslob, Johan D.; Johnson, Rabia; Cai, Hong; Feng, Shirley; Hu, Lanlin; Kosaka, Yuko; Sivaraja, M.; Tep, Samnang; Yang, Hanbiao; Zaharia, Cristiana A.; Evanchik, Marc J.; McDowell, Robert S.

doi:10.1021/ml300335r

Cited by 39 publications

(27 citation statements)

References 21 publications

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“…A set of imidazopyridines have been established through screening against the activity of human FASN and optimized for in vivo stability as well as pharmacokinetic properties. Among them, compound 19 showed a potent dose‐dependent reduction of de novo palmitate synthesis in both in vitro and in vivo systems . Further, another analog in this series, TVB‐3166, was assessed for its antitumor function in several cell lines as well as xenograft tumor models .…”

Section: Recent Approach For Inhibiting Lipogenesis In Transformed Cellsmentioning

confidence: 99%

Aberrant lipid metabolism in cancer cells – the role of oncolipid‐activated signaling

Ray

Roy

2017

The FEBS Journal

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Metabolic activity of malignant cells is very different from that of their nontransformed equivalents, which establishes metabolic reprogramming as an important hallmark of every transformed cell. In particular, the current arena of research in this field aims to understand the regulatory effect of oncogenic signaling on metabolic rewiring in transformed cells in order to exploit this for therapeutic benefit. Alterations in lipid metabolism are one of the main aspects of metabolic rewiring of transformed cells. Up-regulation of several lipogenic enzymes has been reported to be a characteristic of various cancer types. Lysophosphatidic acid (LPA), a simple byproduct of the lipid biosynthesis pathway, has gained immense importance due to its elevated level in several cancers and associated growth-promoting activity. Importantly, a current study revealed its role in increased de novo lipid synthesis through up-regulation of sterol regulatory element-binding protein 1, a master regulator of lipid metabolism. This review summarizes the recent insights in the field of oncolipid LPA-mediated signaling in regard to lipid metabolism in cancers. Future work in this domain is required to understand the up-regulation of the de novo synthesis pathway and the role of its end products in malignant cells. This will open a new arena of research toward the development of specific metabolic inhibitors that can add to the pre-existing chemotherapeutics in order to increase the efficacy of clinical output in cancer patients.

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Section: Recent Approach For Inhibiting Lipogenesis In Transformed Cellsmentioning

confidence: 99%

Aberrant lipid metabolism in cancer cells – the role of oncolipid‐activated signaling

Ray

Roy

2017

The FEBS Journal

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“…Interfering with upstream steps in the fatty acid biosynthesis pathway is another strategy to modulate protein fatty acylation. Imidazopyridine-based inhibitors (compound 19, Figure 3) have been reported that specifically target fatty acid synthase, an enzyme which plays a role in several diseases such as cancer and hepatitis C virus infection [49,50], thereby blocking de novo palmitate synthesis in cell-based assays and in vivo [51]. These compounds may find utility as research tools for pharmacologically validating the function of fatty acid synthase in different disease models.…”

Section: Tools To Perturb Fatty Acylation Of Proteinsmentioning

confidence: 99%

“…A clickable and long alkyl chain analogue of Inhibitors of fatty acyltransferases and fatty acid synthase. Chemical structures for inhibitors of (a) N-myristoyl transferases (DDD85646 [42]), MBOAT proteins such as (b) porcupine (IWP-12 [43], C59 [45], LGK974 [44]), (c) Hhat (RU-SKI 201 [46]) and (d) GOAT (naphthalene-based inhibitor [48], GO-CoA-Tat [47]) and (e) fatty acid synthase (C75, cerulenin, compound 19 [51]). Colors highlight chemotypes critical for activity or those initially identified before lead optimization.…”

Section: Tools To Probe Fatty Acylation Of Proteinsmentioning

confidence: 99%

Synthetic protein lipidation

Hannoush¹

2015

Current Opinion in Chemical Biology

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“…The only FASN inhibitor advanced to clinical trial for the treatment of advanced solid tumors to date is the FASN inhibitor TVB-2640. This molecule is based on a potent imidazopyridine scaffold and also has anti-hepatitis C virus activity (Oslob et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2 + Breast Cancer

Alwarawrah

Hughes

Loiselle

et al. 2016

Cell Chemical Biology

118

111

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Many tumors are dependent on de novo fatty acid synthesis to maintain cell growth. Fatty acid synthase (FASN) catalyzes the final synthetic step of this pathway, and its upregulation is correlated with tumor aggressiveness. The consequences and adaptive responses of acute or chronic inhibition of essential enzymes such as FASN are not fully understood. Herein we identify Fasnall, a thiophenopyrimidine selectively targeting FASN through its co-factor binding sites. Global lipidomics studies with Fasnall showed profound changes in cellular lipid profiles, sharply increasing ceramides, diacylglycerols, and unsaturated fatty acids as well as increasing exogenous palmitate uptake that is deviated more into neutral lipid formation rather than phospholipids. We also showed that the increase in ceramide levels contributes to some extent in the mediation of apoptosis. Consistent with this mechanism of action, Fasnall showed potent anti-tumor activity in the MMTV-Neu model of HER2(+) breast cancer, particularly when combined with carboplatin.

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Imidazopyridine-Based Fatty Acid Synthase Inhibitors That Show Anti-HCV Activity and in Vivo Target Modulation

Cited by 39 publications

References 21 publications

Aberrant lipid metabolism in cancer cells – the role of oncolipid‐activated signaling

Aberrant lipid metabolism in cancer cells – the role of oncolipid‐activated signaling

Synthetic protein lipidation

Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2 + Breast Cancer

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