Abstract 4747: Design and synthesis of a series highly potent and bioavailable FASN KR domain inhibitors for cancer

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

doi:10.1158/1538-7445.am2014-4747

Cited by 6 publications

(4 citation statements)

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“…5A, C), the DEBS DH and other PKS DHs 93–95, 96 (unpublished PDBs: 5J6O, 5IL5, 5IL6, 5HU7, 5HQW) or DH-like domains 97 are rather linear dimers at angles between 170–200°. Further support for an alternate PKS architecture arose from ΨKR/KR structures that revealed an N -terminal β-α-β-α extension of the ΨKR domain 77, 98, 99, 100 relative to mFAS 30, 40, 101 . Finally, an excised, non-naturally occurring ER-ΨKR/KR fragment of the Spinosyn modPKS SpnB, which lacked the DH domain, was crystallized as a domain-swapped monomer with a completely distinct disposition of the ER relative to the KR as compared to mFAS.…”

Section: Fully-reducing Iterative Pksmentioning

confidence: 99%

The architectures of iterative type I PKS and FAS

2018

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Covering: up to mid of 2018 Type I fatty acid synthases (FASs) are giant multienzymes catalyzing all steps of the biosynthesis of fatty acids from acetyl- and malonyl-CoA by iterative precursor extension. Two strikingly different architectures of FAS evolved in yeast (as well as in other fungi and some bacteria) and metazoans. Yeast-type FAS (yFAS) assembles into a barrel-shaped structure of more than 2 MDa molecular weight. Catalytic domains of yFAS are embedded in an extensive scaffolding matrix and arranged around two enclosed reaction chambers. Metazoan FAS (mFAS) is a 540 kDa X-shaped dimer, with lateral reaction clefts, minimal scaffolding and pronounced conformational variability. All naturally occurring yFAS are strictly specialized for the production of saturated fatty acids. The yFAS architecture is not used for the biosynthesis of any other secondary metabolite. On the contrary, mFAS is related at the domain organization level to major classes of polyketide synthases (PKSs). PKSs produce a variety of complex and potent secondary metabolites; they either act iteratively (iPKS), or are linked via directed substrate transfer into modular assembly lines (modPKSs). Here, we review the architectures of yFAS, mFAS, and iPKSs. We rationalize the evolution of the yFAS assembly, and provide examples for re-engineering of yFAS. Recent studies have provided novel insights into the organization of iPKS. A hybrid crystallographic model of a mycocerosic acid synthase-like Pks5 yielded a comprehensive visualization of the organization and dynamics of fully-reducing iPKS. Deconstruction experiments, structural and functional studies of specialized enzymatic domains, such as the product template (PT) and the starter-unit acyltransferase (SAT) domain have revealed functional principles of non-reducing iterative PKS (NR-PKSs). Most recently, a six-domain loading region of an NR-PKS has been visualized at high-resolution together with cryo-EM studies of a trapped loading intermediate. Altogether, these data reveal the related, yet divergent architectures of mFAS, iPKS and also modPKSs. The new insights highlight extensive dynamics, and conformational coupling as key features of mFAS and iPKS and are an important step towards collection of a comprehensive series of snapshots of PKS action.

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Section: Fully-reducing Iterative Pksmentioning

confidence: 99%

The architectures of iterative type I PKS and FAS

2018

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“…None of these compounds have been tested in cancer patients due to limitations imparted by their pharmacologic properties or sideeffect profiles that would limit their clinical development. A new generation of molecules such as GSK2194069 (26), JNJ-54302833 (27), IPI-9119 (28), and TVB-2640 (29) are in development, but only TVB-2640 has moved into the clinic.…”

Section: Fasn Inhibition In Patientsmentioning

confidence: 99%

Molecular Pathways: Fatty Acid Synthase

Jones

Infante

2015

Clinical Cancer Research

225

187

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Therapies that target tumor metabolism represent a new horizon in anticancer therapies. In particular, cancer cells are dependent on the generation of lipids, which are essential for cell membrane synthesis, modification of proteins, and localization of many oncogenic signal transduction enzymes. Because fatty acids are the building blocks of these important lipids, fatty acid synthase (FASN) emerges as a unique oncologic target. FASN inhibitors are being studied preclinically and beginning to transition to first-in-human trials. Early generation FASN inhibitors have been studied preclinically but were limited by their pharmacologic properties and side-effect profiles. A new generation of molecules, including GSK2194069, JNJ-54302833, IPI-9119, and TVB-2640, are in development, but only TVB-2640 has moved into the clinic. FASN inhibition, either alone or in combination, holds promise as a novel therapeutic approach for patients with cancer.

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“…To further test if the anti-cancer activity of Fasnall can be explained by FASN inhibition, we conducted a cell proliferation assay. The antiproliferative effects of FASN inhibitors have been previously demonstrated in special culture conditions with decreased content or complete lack of lipids from fetal bovine serum (FBS) 13,16,23 . GSK2194069 did not affect the proliferation of breast cancer cells in regular, lipid-containing culture conditions (Fig.…”

Section: Fasnall Unlike Fasn Inhibitors Decreases Cancer Cell Prolife...mentioning

confidence: 99%

Identification of Fasnall as a therapeutically effective Complex I inhibitor

Mukha,

Dessain,

O’Connor

et al. 2024

Preprint

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Proliferating cancer cells actively utilize anabolic processes for biomass production, including de novo biosynthesis of amino acids, nucleotides, and fatty acids. The key enzyme of the fatty acid biosynthesis pathway, fatty acid synthase (FASN), is widely recognized as a promising therapeutic target in cancer and other health conditions1,2. Here, we establish a metabolic signature of FASN inhibition using a panel of pharmacological inhibitors (GSK2194069, TVB-2640, TVB-3166, C75, cerulenin, and Fasnall). We find that the activity of commonly used FASN inhibitors is inconsistent with the metabolic signature of FASN inhibition (accumulation of malonate, succinate, malonyl coenzyme A, succinyl coenzyme A, and other metabolic perturbations). Moreover, we show that one of these putative FASN inhibitors, Fasnall, is a respiratory Complex I inhibitor that mimics FASN inhibition through NADH accumulation and consequent depletion of the tricarboxylic acid cycle metabolites. We demonstrate that Fasnall impairs tumor growth in several oxidative phosphorylation-dependent cancer models, including combination therapy-resistant melanoma patient-derived xenografts. Fasnall administration does not reproduce neurological side effects in mice reported for other Complex I inhibitors3,4. Our results have significant implications for understanding the FASN role in human health and disease and provide evidence of therapeutic potential for Complex I inhibitors with fast systemic clearance. Our findings also highlight the continuing need for validation of small molecule inhibitors to distinguish high-quality chemical probes and to expand the understanding of their application.

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Abstract 4747: Design and synthesis of a series highly potent and bioavailable FASN KR domain inhibitors for cancer

Cited by 6 publications

References 0 publications

The architectures of iterative type I PKS and FAS

The architectures of iterative type I PKS and FAS

Molecular Pathways: Fatty Acid Synthase

Identification of Fasnall as a therapeutically effective Complex I inhibitor

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