Design and synthesis of a series of bioavailable fatty acid synthase (FASN) KR domain inhibitors for cancer therapy

Lu, Tianbao; Schubert, Carsten J.; Cummings, Maxwell D.; Bignan, Gilles; Connolly, Peter J.; Smans, Karine; Ludovici, Donald; Parker, Michael H.; Meyer, Christophe; Rocaboy, Christian; Alexander, Richard; Grasberger, Bruce; Breucker, Sabine De; Esser, N.; Fraiponts, Erwin; Gilissen, RMCA mammalogy - Emmanuel; Janssens, Boudewijn; Peeters, Danielle; Nuffel, Luc Van; Vermeulen, Peter; Bischoff, James R.; Meerpoel, Lieven

doi:10.1016/j.bmcl.2018.05.014

Cited by 31 publications

(27 citation statements)

References 17 publications

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“…FASN is transcriptionally regulated by LXR (40), FXR (41), and retinol A (42). Functionally, decreased FASN expression is associated with inhibition of proliferation (43), providing a potential explanation for the regionally specific proliferation response observed in the current study. Furthermore, our results, when considered with recent studies of rodent model of respiratory disease, provide novel evidence for the consideration of LXR agonists as potential therapeutic candidates for the prevention and/or treatment of preterm VILI.…”

Section: Discussionmentioning

confidence: 51%

Preterm Lung Exhibits Distinct Spatiotemporal Proteome Expression at Initiation of Lung Injury

Pereira‐Fantini¹,

Pang²,

Byars

et al. 2019

Am J Respir Cell Mol Biol

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The development of regional lung injury in the preterm lung is not well understood. This study aimed to characterize time-dependent and regionally specific injury patterns associated with early ventilation of the preterm lung using a mass spectrometry-based proteomic approach. Preterm lambs delivered at 124-127 days gestation received 15 or 90 minutes of mechanical ventilation (positive end-expiratory pressure = 8 cm H 2 O, VT = 6-8 ml/kg) and were compared with unventilated control lambs. At study completion, lung tissue was taken from standardized nondependent and dependent regions, and assessed for lung injury via histology, quantitative PCR, and proteomic analysis using Orbitrap-mass spectrometry. Ingenuity pathway analysis software was used to identify temporal and region-specific enrichments in pathways and functions. Apoptotic cell numbers were ninefold higher in nondependent lung at 15 and 90 minutes compared with controls, whereas proliferative cells were increased fourfold in the dependent lung at 90 minutes. The relative gene expression of lung injury markers was increased at 90 minutes in nondependent lung and unchanged in gravity-dependent lung. Within the proteome, the number of differentially expressed proteins was fourfold higher in the nondependent lung than the dependent lung. The number of differential proteins increased over time in both lung regions. A total of 95% of enriched canonical pathways and 94% of enriched cellular and molecular functions were identified only in nondependent lung tissue from the 90-minute ventilation group. In conclusion, complex injury pathways are initiated within the preterm lung after 15 minutes of ventilation and amplified by continuing ventilation. Injury development is region specific, with greater alterations within the proteome of nondependent lung.

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Section: Discussionmentioning

confidence: 51%

Preterm Lung Exhibits Distinct Spatiotemporal Proteome Expression at Initiation of Lung Injury

Pereira‐Fantini¹,

Pang²,

Byars

et al. 2019

Am J Respir Cell Mol Biol

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“…Lu et al have synthesized several FASN inhibitors recently using a structure-based approach guided by X-ray crystallography approach (51). Among them, compound 34 showed a high FASN inhibitory potential and favorable pharmacological features; in addition, it strongly inhibited cell proliferation in several cancer cell lines including A2780 (ovarian), PC3M (prostate), LNCaP (prostate), OCI LY1 (lymphoma), MV4-11 (leukemia/lymphoma/myeloma), H460 (lung), A549 (lung), and MDA-MB-468 (breast), becoming an interesting candidate for future studies (51).…”

Section: Inhibition Of Fatty Acid Synthase In Human Hepatocellular Camentioning

confidence: 99%

Pathogenetic, Prognostic, and Therapeutic Role of Fatty Acid Synthase in Human Hepatocellular Carcinoma

et al. 2019

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Hepatocellular carcinoma (HCC) is one of the most common solid tumors worldwide, characterized by clinical aggressiveness, resistance to conventional chemotherapy, and high lethality. Consequently, there is an urgent need to better delineate the molecular pathogenesis of HCC to develop new preventive and therapeutic strategies against this deadly disease. Noticeably, emerging evidence indicates that proteins involved in lipid biosynthesis are important mediators along the development and progression of HCC in humans and rodents. Here, we provide a comprehensive overview of: (a) The pathogenetic relevance of lipogenic proteins involved in liver carcinogenesis, with a special emphasis on the master fatty acid regulator, fatty acid synthase (FASN); (b) The molecular mechanisms responsible for unrestrained activation of FASN and related fatty acid biosynthesis in HCC; (c) The findings in experimental mouse models of liver cancer and their possible clinical implications; (d) The existing potential therapies targeting FASN. A consistent body of data indicates that elevated levels of lipogenic proteins, including FASN, characterize human hepatocarcinogenesis and are predictive of poor prognosis of HCC patients. Pharmacological or genetic blockade of FASN is highly detrimental for the growth of HCC cells in both in vitro and in vivo models. In conclusion, FASN is involved in the molecular pathogenesis of HCC, where it plays a pivotal role both in tumor onset and progression. Thus, targeted inhibition of FASN and related lipogenesis could be a potentially relevant treatment for human HCC.

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“…FASN is highly expressed in ovarian cancer tissues and is associated with poor prognosis and survival rate (56). Because the majority of cancers rely on the FASN-mediated de novo fatty acid synthesis pathway, FASN could be an attractive therapeutic target, and inhibition of FASN has shown antitumor effects in ovarian cancer (25,57). In tumor cell lines, FASN overexpression was found to cause chemotherapy resistance induced by culture in drug-containing media.…”

Section: Fatty Acid Synthase (Fasn)mentioning

confidence: 99%

Deregulation of Lipid Metabolism: The Critical Factors in Ovarian Cancer

Shen²,

et al. 2020

Front. Oncol.

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Ovarian cancer is one of the most malignant gynecological cancers around the world. In spite of multiple treatment options, the five-year survival rate is still very low. Several metabolism alterations are described as a hallmark in cancers, but alterations of lipid metabolism in ovarian cancer have been paid less attention. To explore new markers/targets for accurate diagnosis, prognosis, and therapeutic treatments based on metabolic enzyme inhibitors, here, we reviewed available literature and summarized several key metabolic enzymes in lipid metabolism of ovarian cancer. In this review, the rate limiting enzymes associated with fatty acid synthesis (FASN, ACC, ACLY, SCD), the lipid degradation related enzymes (MAGL, CPT, 5-LO, COX2), and the receptors related to lipid uptake (FABP4, CD36, LDLR), which promote the development of ovarian cancer, were analyzed and evaluated. We also focused on the review of application of current metabolic enzyme inhibitors for the treatment of ovarian cancer through which the potential therapeutic agents may be developed for ovarian cancer therapy.

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Design and synthesis of a series of bioavailable fatty acid synthase (FASN) KR domain inhibitors for cancer therapy

Cited by 31 publications

References 17 publications

Preterm Lung Exhibits Distinct Spatiotemporal Proteome Expression at Initiation of Lung Injury

Preterm Lung Exhibits Distinct Spatiotemporal Proteome Expression at Initiation of Lung Injury

Pathogenetic, Prognostic, and Therapeutic Role of Fatty Acid Synthase in Human Hepatocellular Carcinoma

Deregulation of Lipid Metabolism: The Critical Factors in Ovarian Cancer

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