Chapter 9. Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors: Bench to Bedside Must Only Go Through Liver

Liu, Gang

doi:10.1039/9781849735322-00249

Cited by 4 publications

(4 citation statements)

References 42 publications

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“…Thus, this possibility of cell or tissue targeting is a very clear prediction from PBIN that we consider has considerable utility in improving the potential therapeutic windows of active drugs, and highlights the need to develop pharmacophores for the more important transporters (Gleeson et al, 2011 ). As with all the other predictions and postdictions of PBIN, the predicted potential for selective, transporter-mediated targeting is amply fulfilled (e.g., Friend and Pangburn, 1987 ; Erion, 2007 ; Oballa et al, 2011 ; Pfefferkorn et al, 2011 ; Powell et al, 2011 ; Ramtohul et al, 2011 ; Reiling et al, 2011 ; Brunschweiger and Hall, 2012 ; Lachance et al, 2012a , b ; Birsoy et al, 2013 ; Filipski et al, 2013 ; Liu, 2013 ; Pfefferkorn, 2013 ; Stevens et al, 2013 ; Tu et al, 2013 ; Sun et al, 2014 ; Tsume et al, 2014 ).…”

Section: Some Further Areas Where the Hypothesis Of Dominant Transpormentioning

confidence: 99%

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

Kell¹,

Oliver²

2014

Front. Pharmacol.

146

169

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One approach to experimental science involves creating hypotheses, then testing them by varying one or more independent variables, and assessing the effects of this variation on the processes of interest. We use this strategy to compare the intellectual status and available evidence for two models or views of mechanisms of transmembrane drug transport into intact biological cells. One (BDII) asserts that lipoidal phospholipid Bilayer Diffusion Is Important, while a second (PBIN) proposes that in normal intact cells Phospholipid Bilayer diffusion Is Negligible (i.e., may be neglected quantitatively), because evolution selected against it, and with transmembrane drug transport being effected by genetically encoded proteinaceous carriers or pores, whose “natural” biological roles, and substrates are based in intermediary metabolism. Despite a recent review elsewhere, we can find no evidence able to support BDII as we can find no experiments in intact cells in which phospholipid bilayer diffusion was either varied independently or measured directly (although there are many papers where it was inferred by seeing a covariation of other dependent variables). By contrast, we find an abundance of evidence showing cases in which changes in the activities of named and genetically identified transporters led to measurable changes in the rate or extent of drug uptake. PBIN also has considerable predictive power, and accounts readily for the large differences in drug uptake between tissues, cells and species, in accounting for the metabolite-likeness of marketed drugs, in pharmacogenomics, and in providing a straightforward explanation for the late-stage appearance of toxicity and of lack of efficacy during drug discovery programmes despite macroscopically adequate pharmacokinetics. Consequently, the view that Phospholipid Bilayer diffusion Is Negligible (PBIN) provides a starting hypothesis for assessing cellular drug uptake that is much better supported by the available evidence, and is both more productive and more predictive.

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Section: Some Further Areas Where the Hypothesis Of Dominant Transpormentioning

confidence: 99%

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

Kell¹,

Oliver²

2014

Front. Pharmacol.

146

169

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“…Recently, Liu published review articles on SCD1 inhibitors for dyslipidemia and obesity. 35,36 Xenon and Novartis. Xenon started its discovery of small molecule SCD1 inhibitors for the treatment of obesity and metabolic syndrome with a high throughput screening campaign that identified a number of pyridin-2-ylpiperazine compounds with micromolar activity against mouse SCD1.…”

Section: ■ Scd1 Inhibitorsmentioning

confidence: 99%

“…This peak was then followed by a rise in papers and presentations starting in 2009. Recently, Liu published review articles on SCD1 inhibitors for dyslipidemia and obesity. , …”

Section: Scd1 Inhibitorsmentioning

confidence: 99%

Opportunities and Challenges in Developing Stearoyl-Coenzyme A Desaturase-1 Inhibitors as Novel Therapeutics for Human Disease

2013

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This review provides an overview of stearoyl-coenzyme A desaturase-1 (SCD1) as a novel therapeutic target for metabolic disorders and other indications. Target validation is reviewed, and limitations due to incomplete knowledge of the relevant biological systems are described. Assay development, particularly for high throughput screening, and characterization of SCD1 inhibition are summarized. The progress and evolution in medicinal chemistry are discussed, specifically focusing on key attributes of the most advanced SCD1 inhibitors described in the primary literature and in patent applications. This work culminated in numerous companies identifying potent selective inhibitors, some of which progressed to early clinical development. The status of current SCD1 drug discovery programs is reviewed. Challenges are discussed, and potential new directions are indicated.

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“…In this case substantial concentration ratios of e.g., hepatocyte: pancreas of 50:1 (Pfefferkorn et al, 2012) and hepatocyte:myocyte of 250,000:1 (Pfefferkorn et al, 2011) could be achieved (a finding hard to explain on the basis of any significant bilayer permeability!). Other examples of tissue-selective drug targeting include a liver-targeted stearoyl desaturase inhibitor (Oballa et al, 2011; Ramtohul et al, 2011; Liu, 2013), various other liver-targeted drugs based on OATPs (Buxhofer-Ausch et al, 2013; Tu et al, 2013), and a prostate-specific targeting of an iodide transporter for radio-iodine-mediated cell killing (Kakinuma et al, 2003). …”

Section: Introductionmentioning

confidence: 99%

Enhancing Drug Efficacy and Therapeutic Index through Cheminformatics-Based Selection of Small Molecule Binary Weapons That Improve Transporter-Mediated Targeting: A Cytotoxicity System Based on Gemcitabine

et al. 2017

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The transport of drug molecules is mainly determined by the distribution of influx and efflux transporters for which they are substrates. To enable tissue targeting, we sought to develop the idea that we might affect the transporter-mediated disposition of small-molecule drugs via the addition of a second small molecule that of itself had no inhibitory pharmacological effect but that influenced the expression of transporters for the primary drug. We refer to this as a “binary weapon” strategy. The experimental system tested the ability of a molecule that on its own had no cytotoxic effect to increase the toxicity of the nucleoside analog gemcitabine to Panc1 pancreatic cancer cells. An initial phenotypic screen of a 500-member polar drug (fragment) library yielded three “hits.” The structures of 20 of the other 2,000 members of this library suite had a Tanimoto similarity greater than 0.7 to those of the initial hits, and each was itself a hit (the cheminformatics thus providing for a massive enrichment). We chose the top six representatives for further study. They fell into three clusters whose members bore reasonable structural similarities to each other (two were in fact isomers), lending strength to the self-consistency of both our conceptual and experimental strategies. Existing literature had suggested that indole-3-carbinol might play a similar role to that of our fragments, but in our hands it was without effect; nor was it structurally similar to any of our hits. As there was no evidence that the fragments could affect toxicity directly, we looked for effects on transporter transcript levels. In our hands, only the ENT1-3 uptake and ABCC2,3,4,5, and 10 efflux transporters displayed measurable transcripts in Panc1 cultures, along with a ribonucleoside reductase RRM1 known to affect gemcitabine toxicity. Very strikingly, the addition of gemcitabine alone increased the expression of the transcript for ABCC2 (MRP2) by more than 12-fold, and that of RRM1 by more than fourfold, and each of the fragment “hits” served to reverse this. However, an inhibitor of ABCC2 was without significant effect, implying that RRM1 was possibly the more significant player. These effects were somewhat selective for Panc cells. It seems, therefore, that while the effects we measured were here mediated more by efflux than influx transporters, and potentially by other means, the binary weapon idea is hereby fully confirmed: it is indeed possible to find molecules that manipulate the expression of transporters that are involved in the bioactivity of a pharmaceutical drug. This opens up an entirely new area, that of chemical genomics-based drug targeting.

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Chapter 9. Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors: Bench to Bedside Must Only Go Through Liver

Cited by 4 publications

References 42 publications

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

Opportunities and Challenges in Developing Stearoyl-Coenzyme A Desaturase-1 Inhibitors as Novel Therapeutics for Human Disease

Enhancing Drug Efficacy and Therapeutic Index through Cheminformatics-Based Selection of Small Molecule Binary Weapons That Improve Transporter-Mediated Targeting: A Cytotoxicity System Based on Gemcitabine

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