Publications by authors named "Colin J Suckling"

60 Publications

Decaprenylphosphoryl-β-d-ribose Oxidase Inhibitors: Expeditious Reconstruction of Suboptimal Hits into a Series with Potent in Vivo Activity.

J Med Chem 2020 03 22;63(5):2557-2576. Epub 2020 Jan 22.

Medicinal Science and Technology, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, U.K.

Decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) is an essential enzyme in and has recently been studied as a potential drug target, with inhibitors progressing to clinical studies. Here we describe the identification of a novel series of morpholino-pyrimidine DprE1 inhibitors. These were derived from a phenotypic high-throughput screening (HTS) hit with suboptimal physicochemical properties. Optimization strategies included scaffold-hopping, synthesis, and evaluation of fragments of the lead compounds and property-focused optimization. The resulting optimized compounds had much improved physicochemical properties and maintained enzyme and cellular potency. These molecules demonstrated potent efficacy in an in vivo tuberculosis murine infection model.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01561DOI Listing
March 2020

Synthetic small molecule analogues of the immunomodulatory Acanthocheilonema viteae product ES-62 promote metabolic homeostasis during obesity in a mouse model.

Mol Biochem Parasitol 2019 12 18;234:111232. Epub 2019 Oct 18.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK. Electronic address:

One of the most rapidly increasing human public health problems is obesity, whose sequelae like type-2 diabetes, represent continuously worsening, life-long conditions. Over the last 15 years, data have begun to emerge from human and more frequently, mouse studies, that support the idea that parasitic worm infection can protect against this condition. We have therefore investigated the potential of two synthetic small molecule analogues (SMAs) of the anti-inflammatory Acanthocheilonema viteae product ES-62, to protect against metabolic dysfunction in a C57BL/6 J mouse model of high calorie diet-induced obesity. We found weekly subcutaneous administration of the SMAs in combination (1 μg of each), starting one week before continuous exposure to high calorie diet (HCD), decreased fasting glucose levels and reversed the impaired glucose clearance observed in male mice, when measured at approximately 7 and 13 weeks after exposure to HCD. Fasting glucose levels were also-reduced in male mice fed a HCD for some 38 weeks when given SMA-treatment 13 weeks after the start of HCD, indicating an SMA-therapeutic potential. For the most part, protective effects were not observed in female mice. SMA treatment also conferred protection against each of reduced ileum villus length and liver fibrosis, but more prominently in female mice. Previous studies in mice indicate that protection against metabolic dysfunction is usually associated with polarisation of the immune system towards a type-2/anti-inflammatory direction but our attempts to correlate improved metabolic parameters with such changes were unsuccessful. Further analysis will therefore be required to define mechanism of action. Nevertheless, overall our data clearly show the potential of the drug-like SMAs as a preventative or treatment for metabolic dysregulation associated with obesity.
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http://dx.doi.org/10.1016/j.molbiopara.2019.111232DOI Listing
December 2019

Selective anti-cancer activity of non-alkylating minor groove binders.

Medchemcomm 2019 Sep 18;10(9):1620-1634. Epub 2019 Jul 18.

Department of Pure and Applied Chemistry , WestCHEM , University of Strathclyde , Glasgow , UK . Email:

Traditional cytotoxic agents which act through a DNA-alkylating mechanism are relatively non-specific, resulting in a small therapeutic window and thus limiting their effectiveness. In this study, we evaluate a panel of 24 non-alkylating Strathclyde Minor Groove Binders (S-MGBs), including 14 novel compounds, for anti-cancer activity against a human colon carcinoma cell line, a cisplatin-sensitive ovarian cancer cell line and a cisplatin-resistant ovarian cancer cell line. A human non-cancerous retinal epithelial cell line was used to measure selectivity of any response. We have identified several S-MGBs with activities comparable to cis-platin and carboplatin, but with better selectivity indices, particularly S-MGB-4, S-MGB-74 and S-MGB-317. Moreover, a comparison of the cis-platin resistant and cis-platin sensitive ovarian cancer cell lines reveals that our S-MGBs do not show cross resistance with cisplatin or carboplatin and that they likely have a different mechanism of action. Finally, we present an initial investigation into the mechanism of action of one compound from this class, S-MGB-4, demonstrating that neither DNA double strand breaks nor the DNA damage stress sensor protein p53 are induced. This indicates that our S-MGBs are unlikely to act through an alkylating or DNA damage response mechanism.
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http://dx.doi.org/10.1039/c9md00268eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478159PMC
September 2019

Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model.

J Med Chem 2019 03 13;62(6):3021-3035. Epub 2019 Mar 13.

Department of Biological and Geographical Sciences, School of Applied Sciences , University of Huddersfield , Huddersfield HD1 3DH , U.K.

Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa because of its huge impact on livestock health. Existing therapies including those based on minor groove binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places because of the emergence of resistant parasites. Consequently, the need for new chemotherapies is urgent. Here, we describe a structurally distinct class of MGBs, Strathclyde MGBs (S-MGBs), which display excellent in vitro activities against the principal causative organisms of AAT: Trypanosoma congolense, and Trypanosoma vivax. We also show the cure of T. congolense-infected mice by a number of these compounds. In particular, we identify S-MGB-234, compound 7, as curative by using two applications of 50 mg/kg intraperitoneally. Crucially, we demonstrate that S-MGBs do not show cross-resistance with the current diamidine drugs and are not internalized via the transporters used by diamidines. This study demonstrates that S-MGBs have significant potential as novel therapeutic agents for AAT.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01847DOI Listing
March 2019

Failure of the Anti-Inflammatory Parasitic Worm Product ES-62 to Provide Protection in Mouse Models of Type I Diabetes, Multiple Sclerosis, and Inflammatory Bowel Disease.

Molecules 2018 Oct 17;23(10). Epub 2018 Oct 17.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.

Parasitic helminths and their isolated secreted products show promise as novel treatments for allergic and autoimmune conditions in humans. Foremost amongst the secreted products is ES-62, a glycoprotein derived from , a filarial nematode parasite of gerbils, which is anti-inflammatory by virtue of covalently-attached phosphorylcholine (PC) moieties. ES-62 has been found to protect against disease in mouse models of rheumatoid arthritis, systemic lupus erythematosus, and airway hyper-responsiveness. Furthermore, novel PC-based synthetic small molecule analogues (SMAs) of ES-62 have recently been demonstrated to show similar anti-inflammatory properties to the parent molecule. In spite of these successes, we now show that ES-62 and its SMAs are unable to provide protection in mouse models of certain autoimmune conditions where other helminth species or their secreted products can prevent disease development, namely type I diabetes, multiple sclerosis and inflammatory bowel disease. We speculate on the reasons underlying ES-62's failures in these conditions and how the negative data generated may help us to further understand ES-62's mechanism of action.
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http://dx.doi.org/10.3390/molecules23102669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222842PMC
October 2018

Discovery of ( S)-3-(3-(3,5-Dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αβ Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis.

J Med Chem 2018 09 14;61(18):8417-8443. Epub 2018 Sep 14.

Department of Pure & Applied Chemistry , University of Strathclyde , 295 Cathedral Street , Glasgow G1 1XL , Scotland, U.K.

A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against αβ, αβ, αβ, αβ, and αβ integrins. Numerous analogs with high affinity and selectivity for the αβ integrin were identified. The analog ( S)-3-(3-(3,5-dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride salt was found to have very high affinity for αβ integrin in a radioligand binding assay (p K = 11), a long dissociation half-life (7 h), very high solubility in saline at pH 7 (>71 mg/mL), and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further clinical investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00959DOI Listing
September 2018

Protection Against Arthritis by the Parasitic Worm Product ES-62, and Its Drug-Like Small Molecule Analogues, Is Associated With Inhibition of Osteoclastogenesis.

Front Immunol 2018 14;9:1016. Epub 2018 May 14.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.

The immunomodulatory actions of parasitic helminth excretory-secretory (ES) products that serendipitously protect against development of chronic inflammatory disorders are well established: however, knowledge of the interaction between ES products and the host musculoskeletal system in such diseases is limited. In this study, we have focused on ES-62, a glycoprotein secreted by the rodent filarial nematode that is immunomodulatory by virtue of covalently attached phosphorylcholine (PC) moieties, and also two synthetic drug-like PC-based small molecule analogues (SMAs) that mimic ES-62's immunomodulatory activity. We have previously shown that each of these molecules prevents development of pathology in collagen-induced arthritis (CIA), a model of the musculoskeletal disease rheumatoid arthritis (RA) and reflecting this, we now report that ES-62 and its SMAs, modify bone remodeling by altering bone marrow progenitors and thus impacting on osteoclastogenesis. Consistent with this, we find that these molecules inhibit functional osteoclast differentiation . Furthermore, this appears to be achieved by induction of anti-oxidant response gene expression, thereby resulting in reduction of the reactive oxygen species production that is necessary for the increased osteoclastogenesis witnessed in musculoskeletal diseases like RA.
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http://dx.doi.org/10.3389/fimmu.2018.01016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967578PMC
July 2019

Synthetic analogues of the parasitic worm product ES-62 reduce disease development in in vivo models of lung fibrosis.

Acta Trop 2018 Sep 23;185:212-218. Epub 2018 May 23.

Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), University of Strathclyde, Glasgow, G4 0RE, UK. Electronic address:

Parasitic worms are receiving much attention as a potential new therapeutic approach to treating autoimmune and allergic conditions but concerns remain regarding their safety. As an alternative strategy, we have focused on the use of defined parasitic worm products and recently taken this one step further by designing drug-like small molecule analogues of one such product, ES-62, which is anti-inflammatory by virtue of covalently attached phosphorylcholine moieties. Previously, we have shown that ES-62 mimics are efficacious in protecting against disease in mouse models of rheumatoid arthritis, systemic lupus erythematosus and skin and lung allergy. Given the potential role of chronic inflammation in fibrosis, in the present study we have focused our attention on lung fibrosis, a debilitating condition for which there is no cure and which in spite of treatment slowly gets worse over time. Two mouse models of fibrosis - bleomycin-induced and LPS-induced - in which roles for inflammation have been implicated were adopted. Four ES-62 analogues were tested - 11a and 12b, previously shown to be active in mouse models of allergic and autoimmune disease and 16b and AIK-29/62 both of which are structurally related to 11a. All four compounds were found to significantly reduce disease development in both fibrosis models, as shown by histopathological analysis of lung tissue, indicating their potential as treatments for this condition.
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http://dx.doi.org/10.1016/j.actatropica.2018.05.015DOI Listing
September 2018

Small Molecule Analogues of the parasitic worm product ES-62 interact with the TIR domain of MyD88 to inhibit pro-inflammatory signalling.

Sci Rep 2018 02 1;8(1):2123. Epub 2018 Feb 1.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK.

ES-62 is a protein secreted by the parasitic worm Acanthocheilonema viteae that is anti-inflammatory by virtue of covalently attached phosphorylcholine. Previously we have reported that drug-like Small Molecule Analogues (SMAs) of its phosphorylcholine moiety can mimic ES-62 in protecting against disease development in certain mouse models of autoimmune and allergic conditions, due to them causing partial degradation of the TLR/IL-1R adaptor MyD88. We have now taken a molecular modelling approach to investigating the mechanism underlying this effect and this predicts that the SMAs interact directly with the MyD88 TIR domain. Further support for this is provided by assay of LPS-induced MyD88/NF-κB-driven secreted alkaline phosphatase (SEAP) reporter activity in commercially-available stably transfected (TLR4-MD2-NF-κB-SEAP) HEK293 cells, as SMA12b-mediated inhibition of such SEAP activity is blocked by its pre-incubation with recombinant MyD88-TIR domain. Direct binding of SMA12b to the TIR domain is also shown to inhibit homo-dimerization of the adaptor, an event that can explain the observed degradation of the adaptor and inhibition of subsequent downstream signalling. Thus, these new data identify initial events by which drug-like ES-62 SMAs, which we also demonstrate are able to inhibit cytokine production by human cells, homeostatically maintain "safe" levels of MyD88 signalling.
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http://dx.doi.org/10.1038/s41598-018-20388-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794923PMC
February 2018

Evaluation of minor groove binders (MGBs) as novel anti-mycobacterial agents and the effect of using non-ionic surfactant vesicles as a delivery system to improve their efficacy.

J Antimicrob Chemother 2017 Dec;72(12):3334-3341

University of Cape Town, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa.

Objectives: The slow development of major advances in drug discovery for the treatment of Mycobacterium tuberculosis (Mtb) infection suggests a compelling need for evaluation of more effective drug therapies against TB. New classes of drugs are constantly being evaluated for anti-mycobacterial activity with currently a very limited number of new drugs approved for TB treatment. Minor groove binders (MGBs) have previously revealed promising antimicrobial activity against various infectious agents; however, they have not yet been screened against Mtb.

Methods: The mycobactericidal activity of 96 MGB compounds against Mtb was determined using an H37Rv-GFP microplate assay. MGB hits were screened for their intracellular mycobactericidal efficacy against the clinical Beijing Mtb strain HN878 in bone-marrow-derived macrophages using standard cfu counting. Cell viability was assessed by CellTiter-Blue assays. Selected MGBs were encapsulated into non-ionic surfactant vesicles (NIVs) for drug delivery system evaluation.

Results: H37Rv-GFP screening yielded a hit-list of seven compounds at an MIC99 of between 0.39 and 1.56 μM. MGB-362 and MGB-364 displayed intracellular mycobactericidal activity against Mtb HN878 at an MIC50 of 4.09 and 4.19 μM, respectively, whilst being non-toxic. Subsequent encapsulation into NIVs demonstrated a 1.6- and 2.1-fold increased intracellular mycobacterial activity, similar to that of rifampicin when compared with MGB-alone formulation.

Conclusions: MGB anti-mycobacterial activities together with non-toxic properties indicate that MGB compounds constitute an important new class of drug/chemical entity, which holds promise in future anti-TB therapy. Furthermore, the ability of NIVs to better deliver entrapped MGB compounds to an intracellular Mtb infection suggests further preclinical evaluation is warranted.
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http://dx.doi.org/10.1093/jac/dkx326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890746PMC
December 2017

Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers.

J Med Chem 2017 08 15;60(16):7043-7066. Epub 2017 Aug 15.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.

IKKβ plays a central role in the canonical NF-kB pathway, which has been extensively characterized. The role of IKKα in the noncanonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKKβ, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKKα over IKKβ. Herein, we report for the first time a series of novel, potent, and selective inhibitors of IKKα. We demonstrate effective target engagement and selectivity with IKKα in U2OS cells through inhibition of IKKα-driven p100 phosphorylation in the noncanonical NF-kB pathway without affecting IKKβ-dependent IKappa-Bα loss in the canonical pathway. These compounds represent the first chemical tools that can be used to further characterize the role of IKKα in cellular signaling, to dissect this from IKKβ and to validate it in its own right as a target in inflammatory diseases.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578373PMC
August 2017

An evaluation of Minor Groove Binders as anti-fungal and anti-mycobacterial therapeutics.

Eur J Med Chem 2017 Aug 17;136:561-572. Epub 2017 May 17.

WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.

This study details the synthesis and biological evaluation of a collection of 19 structurally related Minor Groove Binders (MGBs), derived from the natural product distamycin, which were designed to probe antifungal and antimycobacterial activity. From this initial set, we report several MGBs that are worth more detailed investigation and optimisation. MGB-4, MGB-317 and MGB-325 have promising MICs of 2, 4 and 0.25 μg/mL, respectively, against the fungus C. neoformans.MGB-353 and MGB-354 have MICs of 3.1 μM against the mycobacterium M. tuberculosis. The selectivity and activity of these compounds is related to their physicochemical properties and the cell wall/membrane characteristics of the infective agents.
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http://dx.doi.org/10.1016/j.ejmech.2017.05.039DOI Listing
August 2017

Dendritic cells provide a therapeutic target for synthetic small molecule analogues of the parasitic worm product, ES-62.

Sci Rep 2017 05 10;7(1):1704. Epub 2017 May 10.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.

ES-62, a glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae, subverts host immune responses towards anti-inflammatory phenotypes by virtue of covalently attached phosphorylcholine (PC). The PC dictates that ES-62 exhibits protection in murine models of inflammatory disease and hence a library of drug-like PC-based small molecule analogues (SMAs) was synthesised. Four sulfone-containing SMAs termed 11a, 11e, 11i and 12b were found to reduce mouse bone marrow-derived dendritic cell (DC) pathogen-associated molecular pattern (PAMP)-induced pro-inflammatory cytokine production, inhibit NF-κB p65 activation, and suppress LPS-induced up-regulation of CD40 and CD86. Active SMAs also resulted in a DC phenotype that exhibited reduced capacity to prime antigen (Ag)-specific IFN-γ production during co-culture with naïve transgenic TCR DO.11.10 T cells in vitro and reduced their ability, following adoptive transfer, to prime the expansion of Ag-specific T lymphocytes, specifically T17 cells, in vivo. Consistent with this, mice receiving DCs treated with SMAs exhibited significantly reduced severity of collagen-induced arthritis and this was accompanied by a significant reduction in IL-17 cells in the draining lymph nodes. Collectively, these studies indicate that drug-like compounds that target DCs can be designed from parasitic worm products and demonstrate the potential for ES-62 SMA-based DC therapy in inflammatory disease.
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http://dx.doi.org/10.1038/s41598-017-01651-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431997PMC
May 2017

Four pyrrole derivatives used as building blocks in the synthesis of minor-groove binders.

Acta Crystallogr E Crystallogr Commun 2017 Feb 27;73(Pt 2):254-259. Epub 2017 Jan 27.

Westchem, Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland.

The title nitro-pyrrole-based compounds, CHNO, (I) (ethyl 4-nitro-1-pyrrole-2-carboxyl-ate), its derivative CHNO, (II) [ethyl 4-nitro-1-(4-pent-yn-yl)-1-pyrrole-2-carboxyl-ate], CHNO, (III) {-[3-(di-methyamino)prop-yl]-1-isopentyl-4-nitro-1-pyrrole-2-carboxamide}, and CHNO, (IV) {1-(3-azido-prop-yl)-4-(1-methyl-4-nitro-1-pyrrole-2-carboxamido)--[2-(morpholin-4-yl)eth-yl]-1-pyrrole-2-carboxamide}, are inter-mediates used in the synthesis of modified DNA minor-groove binders. In all four compounds, the nitro groups lie in the plane of the pyrrole ring. In compounds (I) and (II), the ester groups also lie in the plane of the pyrrole ring. In compound (III), both of the other substituents lie out of the plane of the pyrrole ring. In the case of compound (IV), the coplanarity extends to the second pyrrole ring and through both amide groups. In the crystals of all four compounds, layer-like structures are formed, a combination of N-H⋯O and C-H⋯O hydrogen bonds for (I), (III) and (IV), but by only C-H⋯O hydrogen bonds for (II).
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http://dx.doi.org/10.1107/S2056989017001177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290577PMC
February 2017

Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe.

J Med Chem 2017 01 9;60(2):695-709. Epub 2017 Jan 9.

WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, United Kingdom.

p300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01566DOI Listing
January 2017

An evaluation of Minor Groove Binders as anti-lung cancer therapeutics.

Bioorg Med Chem Lett 2016 08 16;26(15):3478-86. Epub 2016 Jun 16.

WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.

A series of 47 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for anti-lung cancer activity by screening against the melanoma cancer cell line B16-F10. Five compounds have been found to possess significant activity, more so than a standard therapy, Gemcitabine. Moreover, one compound has been found to have an activity around 70-fold that of Gemcitabine and has a favourable selectivity index of greater than 125. Furthermore, initial studies have revealed this compound to be metabolically stable and thus it represents a lead for further optimisation towards a novel treatment for lung cancer.
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http://dx.doi.org/10.1016/j.bmcl.2016.06.040DOI Listing
August 2016

Selective anti-malarial minor groove binders.

Bioorg Med Chem Lett 2016 07 13;26(14):3326-3329. Epub 2016 May 13.

WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.

A set of 31 DNA minor groove binders (MGBs) with diverse structural features relating to both physical chemical properties and DNA binding sequence preference has been evaluated as potential drugs to treat Plasmodium falciparum infections using a chloroquine sensitive strain (3D7) and a chloroquine resistant strain (Dd2) in comparison with human embryonic kidney (HEK) cells as an indicator of mammalian cell toxicity. MGBs with an alkene link between the two N-terminal building blocks were demonstrated to be most active with IC50 values in the range 30-500nM and therapeutic ratios in the range 10->500. Many active compounds contained a C-alkylthiazole building block. Active compounds with logD7.4 values of approximately 3 or 7 were identified. Importantly the MGBs tested were essentially equally effective against both chloroquine sensitive and resistant strains. The results show that suitably designed MGBs have the potential for development into clinical candidates for antimalarial drugs effective against resistant strains of Plasmodia.
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http://dx.doi.org/10.1016/j.bmcl.2016.05.039DOI Listing
July 2016

An evaluation of Minor Groove Binders as anti-Trypanosoma brucei brucei therapeutics.

Eur J Med Chem 2016 Jun 29;116:116-125. Epub 2016 Mar 29.

WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.

A series of 32 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for activity against Trypanosoma brucei brucei. Four compounds have been found to possess significant activity, in the nanomolar range, and represent hits for further optimisation towards novel treatments for Human and Animal African Trypanosomiases. Moreover, SAR indicates that the head group linking moiety is a significant modulator of biological activity.
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http://dx.doi.org/10.1016/j.ejmech.2016.03.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872591PMC
June 2016

Structurally Diverse Mitochondrial Branched Chain Aminotransferase (BCATm) Leads with Varying Binding Modes Identified by Fragment Screening.

J Med Chem 2016 Mar 16;59(6):2452-67. Epub 2016 Mar 16.

Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.

Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars showed significant diversity in their binding modes. The hits identified were supplemented by searching and screening of additional analogues, which enabled the gathering of further X-ray data where the original hits had not produced liganded structures. The fragment hits were optimized using structure-based design, with some transfer of information between series, which enabled the identification of ligand efficient lead molecules with micromolar levels of inhibition, cellular activity, and good solubility.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01607DOI Listing
March 2016

Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 2. Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives.

J Med Chem 2016 Feb 15;59(4):1370-87. Epub 2016 Jan 15.

Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.

Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01538DOI Listing
February 2016

Crystal structure of N,N-dimethyl-2-[(4-methyl-benz-yl)sulfon-yl]ethanamine.

Acta Crystallogr E Crystallogr Commun 2015 Jul 6;71(Pt 7):757-9. Epub 2015 Jun 6.

Westchem, Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland.

In the crystal, the title compound, C12H19NO2S, has a disordered structure with two equally populated conformations of the amine fragment. A pair of weak C-H⋯O inter-molecular inter-actions between the CH2 and SO2 groups gives a one-dimensional supra-molecular structure that propagates through translation along the a-axis direction.
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http://dx.doi.org/10.1107/S2056989015010233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518984PMC
July 2015

The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits.

J Med Chem 2015 Sep 2;58(18):7140-63. Epub 2015 Jul 2.

GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.

The hybridization of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm) based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimization of potency with maintenance of ligand efficiency, while the focus on physicochemical properties delivered compounds with excellent pharmacokinetic exposure that enabled a proof of concept experiment in mice. Oral administration of 2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile 61 significantly raised the circulating levels of the branched-chain amino acids leucine, isoleucine, and valine in this acute study.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00313DOI Listing
September 2015

Prophylactic and therapeutic treatment with a synthetic analogue of a parasitic worm product prevents experimental arthritis and inhibits IL-1β production via NRF2-mediated counter-regulation of the inflammasome.

J Autoimmun 2015 Jun 11;60:59-73. Epub 2015 May 11.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK. Electronic address:

Rheumatoid arthritis (RA) remains a debilitating autoimmune condition as many patients are refractory to existing conventional and biologic therapies, and hence successful development of novel treatments remains a critical requirement. Towards this, we now describe a synthetic drug-like small molecule analogue, SMA-12b, of an immunomodulatory parasitic worm product, ES-62, which acts both prophylactically and therapeutically against collagen-induced arthritis (CIA) in mice. Mechanistic analysis revealed that SMA-12b modifies the expression of a number of inflammatory response genes, particularly those associated with the inflammasome in mouse bone marrow-derived macrophages and indeed IL-1β was the most down-regulated gene. Consistent with this, IL-1β was significantly reduced in the joints of mice with CIA treated with SMA-12b. SMA-12b also increased the expression of a number of genes associated with anti-oxidant responses that are controlled by the transcription factor NRF2 and critically, was unable to inhibit expression of IL-1β by macrophages derived from the bone marrow of NRF2(-/-) mice. Collectively, these data suggest that SMA-12b could provide the basis of an entirely novel approach to fulfilling the urgent need for new treatments for RA.
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http://dx.doi.org/10.1016/j.jaut.2015.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459730PMC
June 2015

Protective effect of small molecule analogues of the Acanthocheilonema viteae secreted product ES-62 on oxazolone-induced ear inflammation.

Exp Parasitol 2015 Nov 30;158:18-22. Epub 2015 Mar 30.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK. Electronic address:

ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following their administration before oxazolone sensitisation and before oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered before challenge. Histological analysis of the ears showed elevated cellular infiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNγ mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed.
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http://dx.doi.org/10.1016/j.exppara.2015.03.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659540PMC
November 2015

Novel TPP-riboswitch activators bypass metabolic enzyme dependency.

Front Chem 2014 28;2:53. Epub 2014 Jul 28.

Life and Medical Sciences Institute, University of Bonn Bonn, Germany.

Riboswitches are conserved regions within mRNA molecules that bind specific metabolites and regulate gene expression. TPP-riboswitches, which respond to thiamine pyrophosphate (TPP), are involved in the regulation of thiamine metabolism in numerous bacteria. As these regulatory RNAs are often modulating essential biosynthesis pathways they have become increasingly interesting as promising antibacterial targets. Here, we describe thiamine analogs containing a central 1,2,3-triazole group to induce repression of thiM-riboswitch dependent gene expression in different E. coli strains. Additionally, we show that compound activation is dependent on proteins involved in the metabolic pathways of thiamine uptake and synthesis. The most promising molecule, triazolethiamine (TT), shows concentration dependent reporter gene repression that is dependent on the presence of thiamine kinase ThiK, whereas the effect of pyrithiamine (PT), a known TPP-riboswitch modulator, is ThiK independent. We further show that this dependence can be bypassed by triazolethiamine-derivatives that bear phosphate-mimicking moieties. As triazolethiamine reveals superior activity compared to pyrithiamine, it represents a very promising starting point for developing novel antibacterial compounds that target TPP-riboswitches. Riboswitch-targeting compounds engage diverse endogenous mechanisms to attain in vivo activity. These findings are of importance for the understanding of compounds that require metabolic activation to achieve effective riboswitch modulation and they enable the design of novel compound generations that are independent of endogenous activation mechanisms.
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http://dx.doi.org/10.3389/fchem.2014.00053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112796PMC
August 2014

Recognition of the DNA minor groove by thiazotropsin analogues.

Chembiochem 2014 Sep 16;15(13):1978-90. Epub 2014 Jul 16.

Department of Pharmacy, An-Najah National University, University Street, Nablus (Palestine); Present address: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 2J7 (Canada).

Solution-phase self-association characteristics and DNA molecular-recognition properties are reported for three close analogues of minor-groove-binding ligands from the thiazotropsin class of lexitropsin molecules; they incorporate isopropyl thiazole as a lipophilic building block. Thiazotropsin B (AcImPy(iPr) ThDp) shows similar self-assembly characteristics to thiazotropsin A (FoPyPy(iPr) ThDp), although it is engineered, by incorporation of imidazole in place of N-methyl pyrrole, to swap its DNA recognition target from 5'-ACTAGT-3' to 5'-ACGCGT-3'. Replacement of the formamide head group in thiazotropsin A by nicotinamide in AIK-18/51 results in a measureable difference in solution-phase self-assembly character and substantially enhanced DNA association characteristics. The structures and associated thermodynamic parameters of self-assembled ligand aggregates and their complexes with their respective DNA targets are considered in the context of cluster targeting of DNA by minor-groove complexes.
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http://dx.doi.org/10.1002/cbic.201402202DOI Listing
September 2014

Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1.

J Med Chem 2014 Aug 29;57(15):6479-94. Epub 2014 Jul 29.

WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.

The treatment of Human African trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important; pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp., has been identified as a candidate target, and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from Trypanosoma brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. Eight compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus, although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development.
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http://dx.doi.org/10.1021/jm500483bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136963PMC
August 2014

Small molecule analogues of the immunomodulatory parasitic helminth product ES-62 have anti-allergy properties.

Int J Parasitol 2014 Aug 12;44(9):669-74. Epub 2014 Jun 12.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, Scotland, UK. Electronic address:

ES-62, a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, exhibits anti-inflammatory properties by virtue of covalently attached phosphorylcholine moieties. Screening of a library of ES-62 phosphorylcholine-based small molecule analogues (SMAs) revealed that two compounds, termed 11a and 12b, mirrored the helminth product both in inhibiting mast cell degranulation and cytokine responses in vitro and in preventing ovalbumin-induced Th2-associated airway inflammation and eosinophil infiltration of the lungs in mice. Furthermore, the two SMAs inhibited neutrophil infiltration of the lungs when administered therapeutically. ES-62-SMAs 11a and 12b thus represent starting points for novel drug development for allergies such as asthma.
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http://dx.doi.org/10.1016/j.ijpara.2014.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119935PMC
August 2014

Communication between the zinc and tetrahydrobiopterin binding sites in nitric oxide synthase.

Biochemistry 2014 Jul 17;53(25):4216-23. Epub 2014 Jun 17.

Departments of †Molecular Biology and Biochemistry, ‡Chemistry, and §Pharmaceutical Sciences, University of California , Irvine, California 92697-3900, United States.

The nitric oxide synthase (NOS) dimer is stabilized by a Zn(2+) ion coordinated to four symmetry-related Cys residues exactly along the dimer 2-fold axis. Each of the two essential tetrahydrobiopterin (H4B) molecules in the dimer interacts directly with the heme, and each H4B molecule is ~15 Å from the Zn(2+). We have determined the crystal structures of the bovine endothelial NOS dimer oxygenase domain bound to three different pterin analogues, which reveal an intimate structural communication between the H4B and Zn(2+) sites. The binding of one of these compounds, 6-acetyl-2-amino-7,7-dimethyl-7,8-dihydro-4(3H)-pteridinone (1), to the pterin site and Zn(2+) binding are mutually exclusive. Compound 1 both directly and indirectly disrupts hydrogen bonding between key residues in the Zn(2+) binding motif, resulting in destabilization of the dimer and a complete disruption of the Zn(2+) site. Addition of excess Zn(2+) stabilizes the Zn(2+) site at the expense of weakened binding of 1. The unique structural features of 1 that disrupt the dimer interface are extra methyl groups that extend into the dimer interface and force a slight opening of the dimer, thus resulting in disruption of the Zn(2+) site. These results illustrate a very delicate balance of forces and structure at the dimer interface that must be maintained to properly form the Zn(2+), pterin, and substrate binding sites.
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http://dx.doi.org/10.1021/bi5003986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082377PMC
July 2014

Designing anti-inflammatory drugs from parasitic worms: a synthetic small molecule analogue of the Acanthocheilonema viteae product ES-62 prevents development of collagen-induced arthritis.

J Med Chem 2013 Dec 25;56(24):9982-10002. Epub 2013 Nov 25.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0RE, U.K.

In spite of increasing evidence that parasitic worms may protect humans from developing allergic and autoimmune diseases and the continuing identification of defined helminth-derived immunomodulatory molecules, to date no new anti-inflammatory drugs have been developed from these organisms. We have approached this matter in a novel manner by synthesizing a library of drug-like small molecules based upon phosphorylcholine, the active moiety of the anti-inflammatory Acanthocheilonema viteae product, ES-62, which as an immunogenic protein is unsuitable for use as a drug. Following preliminary in vitro screening for inhibitory effects on relevant macrophage cytokine responses, a sulfone-containing phosphorylcholine analogue (11a) was selected for testing in an in vivo model of inflammation, collagen-induced arthritis (CIA). Testing revealed that 11a was as effective as ES-62 in protecting DBA/1 mice from developing CIA and mirrored its mechanism of action in downregulating the TLR/IL-1R transducer, MyD88. 11a is thus a novel prototype for anti-inflammatory drug development.
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http://dx.doi.org/10.1021/jm401251pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4125414PMC
December 2013