Implications of endogenous roles of transporters for drug discovery: hitchhiking and metabolite-likeness

Kell, Douglas B.

doi:10.1038/nrd.2015.44

Cited by 35 publications

(26 citation statements)

References 11 publications

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“…Furthermore, drugs designed with “metabolite-likeness”(75) have a greater chance of achieving standards of efficacy such as Lipinski's rule of five(76), suggesting an important role for SLC transporters in drug uptake. Several important cancer drugs have known transporters.…”

Section: Discussionmentioning

confidence: 99%

Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155

Nyquist

Corella

Burns

et al. 2017

Molecular Cancer Research

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Androgen receptor (AR) signaling is fundamental to prostate cancer and is the dominant therapeutic target in metastatic disease. However, stringent androgen deprivation therapy (ADT) regimens decrease quality of life and have been largely unsuccessful in curtailing mortality. Recent clinical and pre-clinical studies have taken advantage of the dichotomous ability of AR signaling to elicit growth-suppressive and differentiating effects by administering hyper-physiological levels of testosterone. In this study, high-throughput drug screening identified a potent synergy between high-androgen therapy and YM155, a transcriptional inhibitor of Survivin (BIRC5). This interaction was mediated by the direct transcriptional upregulation of the YM155 transporter SLC35F2 by the AR. Androgen-mediated YM155-induced cell death was completely blocked by the overexpression of multidrug resistance (MDR) transporter ABCB1. SLC35F2 expression was significantly correlated with intra-tumor androgen levels in four distinct patient-derived xenografts (PDX) models, and with AR-activity score in a large gene expression dataset of castration resistant metastases. A subset of tumors had significantly elevated SLC35F2 expression and therefore, may identify patients who are highly responsive to YM155 treatment.Implications-The combination of androgen therapy with YM155 represents a novel drug synergy, and SLC35F2 may serve as a clinical biomarker of response to YM155.

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Section: Discussionmentioning

confidence: 99%

Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155

Nyquist

Corella

Burns

et al. 2017

Molecular Cancer Research

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“…We recently identified OCT1 as a high-capacity transporter of thiamine in the liver and showed that the transporter plays a key role in modulating hepatic energy status and lipid content. 2 Although the transporter clearly has important endogenous functions, 2,3 OCT1 has been characterized primarily as a drug transporter, capable of transporting a wide variety of prescription drugs, including the antidiabetic drug metformin and the opioid analgesic morphine. Genetic variants of OCT1 with reduced function have been associated with decreased response to metformin 4 as well as high systemic plasma levels of morphine and the active metabolite of the opioidergic drug tramadol.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Competitive and Noncompetitive Ligands of the Organic Cation Transporter 1 (OCT1; SLC22A1)

et al. 2017

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Organic cation transporter 1 (OCT1) plays a critical role in the hepatocellular uptake of structurally diverse endogenous compounds and xenobiotics. Here we identified competitive and noncompetitive OCT1-interacting ligands in a library of 1780 prescription drugs by combining in silico and in vitro methods. Ligands were predicted by docking against a comparative model based on a eukaryotic homologue. In parallel, high-throughput screening (HTS) was conducted using the fluorescent probe substrate ASP+ in cells overexpressing human OCT1. Thirty competitive OCT1 ligands, defined as ligands predicted in silico as well as found by HTS, were identified. Of the 167 ligands identified by HTS, five were predicted to potentially cause clinical drug interactions. Finally, virtual screening of 29 332 metabolites predicted 146 competitive OCT1 ligands, of which an endogenous neurotoxin, 1-benzyl-1,2,3,4-tetrahydroisoquinoline, was experimentally validated. In conclusion, by combining docking and in vitro HTS, competitive and noncompetitive ligands of OCT1 can be predicted.

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“…Given the overwhelming evidence [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] that pharmaceutical drugs must and do exploit endogenous transporters that normally transport biological metabolites, and that normally any diffusion of such drugs through the phospholipid bilayer portions of undamaged biological membranes is negligible [1; 3; 5-7; 10; 11; 13; 21], we [2; 22-24] and others (e.g. [16; 25-30]) have been assessing the extent to which marketed (hence successful) xenobiotic drugs are similar in structural terms to endogenous human metabolites (that we sometimes refer to as 'endogenites').…”

Section: Introductionmentioning

confidence: 99%

Consensus rank orderings of molecular fingerprints illustrate the ‘most genuine’ similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

O’Hagan

Kell

2017

Preprint

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We compare several molecular fingerprint encodings for marketed, small molecule drugs, and assess how their rank order varies with the fingerprint in terms of the Tanimoto similarity to the most similar endogenous human metabolite as taken from Recon2. For the great majority of drugs, the rank order varies very greatly depending on the encoding used, and also somewhat when the Tanimoto similarity (TS) is replaced by the Tversky similarity. However, for a subset of such drugs, amounting to some 10% of the set and a Tanimoto similarity of ~0.8 or greater, the similarity coefficient is relatively robust to the encoding used. This leads to a metric that, while arbitrary, suggests that a Tanimoto similarity of 0.75-0.8 or greater genuinely does imply a considerable structural similarity of two molecules in the drug-endogenite space. Although comparatively few (<10% of) marketed drugs are, in this sense, robustly similar to an endogenite, there is often at least one encoding with which they are genuinely similar (e.g. TS > 0.75). This is referred to as the Take Your Pick Improved Cheminformatic Analytical Likeness or TYPICAL encoding, and on this basis some 66% of drugs are within a TS of 0.75 to an endogenite.We next explicitly recognise that natural evolution will have selected for the ability to transport dietary substances, including plant, animal and microbial 'secondary' metabolites, that are of benefit to the host. These should also be explored in terms of their closeness to marketed drugs. We thus compared the TS of marketed drugs with the contents of various databases of natural products. When this is done, we find that some 80% of marketed drugs are within a TS of 0.7 to a natural product, even using just the MACCS encoding. For patterned and TYPICAL encodings, 80% and 98% of drugs are within a TS of 0.8 to (an endogenite or) an exogenous natural product. This implies strongly that it is these exogeneous (dietary and medicinal) natural products that are more to be seen as the 'natural' substrates of drug transporters (as is recognised, for instance, for the solute carrier SLC22A4 and ergothioneine). This novel analysis casts an entirely different light on the kinds of natural molecules that are to be seen as most like marketed drugs, and hence potential transporter substrates, and further suggests that a renewed exploitation of natural products as drug scaffolds would be amply rewarded.

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Implications of endogenous roles of transporters for drug discovery: hitchhiking and metabolite-likeness

Cited by 35 publications

References 11 publications

Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155

Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155

Discovery of Competitive and Noncompetitive Ligands of the Organic Cation Transporter 1 (OCT1; SLC22A1)

Consensus rank orderings of molecular fingerprints illustrate the ‘most genuine’ similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

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