1. VER-246608, a novel pan-isoform ATP competitive inhibitor of pyruvate dehydrogenase kinase, disrupts Warburg metabolism and induces context-dependent cytostasis in cancer cells.

    Oncotarget 5(24):12862 (2014) PMID 25404640 PMCID PMC4350332

    Pyruvate dehydrogenase kinase (PDK) is a pivotal enzyme in cellular energy metabolism that has previously been implicated in cancer through both RNAi based studies and clinical correlations with poor prognosis in several cancer types. Here, we report the discovery of a novel and selective ATP co...
  2. Off-rate screening (ORS) by surface plasmon resonance. An efficient method to kinetically sample hit to lead chemical space from unpurified reaction products.

    Journal of medicinal and pharmaceutical chemistry 57(7):2845 (2014) PMID 24520903

    The dissociation rate constant kd (off-rate) is the component of ligand-protein binding with the most significant potential to enhance compound potency. Here we provide theoretical and empirical data to show that this parameter can be determined accurately from unpurified reaction products conta...
  3. Fragment screening by weak affinity chromatography: comparison with established techniques for screening against HSP90.

    Analytical chemistry 85(14):6756 (2013) PMID 23806099

    The increasing use of fragment-based lead discovery (FBLD) in industry as well as in academia creates a high demand for sensitive and reliable methods to detect the binding of fragments to act as starting points in drug discovery programs. Nuclear magnetic resonance (NMR), surface plasmon resona...
  4. Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization

    Bioorganic & Medicinal Chemistry 20(22):6770 (2012)

  5. Targeting conserved water molecules: design of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization.

    Bioorganic & Medicinal Chemistry 20(22):6770 (2012) PMID 23018093

    Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening ...
  6. Fatty acid amide hydrolase inhibitors. 3: tetra-substituted azetidine ureas with in vivo activity.

    Bioorganic & Medicinal Chemistry Letters 22(2):901 (2012) PMID 22209458

    We describe here our attempts to optimise the human fatty acid amide hydrolase (FAAH) inhibition and physicochemical properties of our previously reported tetrasubstituted azetidine urea FAAH inhibitor, VER-156084. We describe the SAR of a series of analogues and conclude with the demonstration ...
  7. Fatty acid amide hydrolase inhibitors. 3: Tetra-substituted azetidine ureas with in vivo activity

    Bioorganic & Medicinal Chemistry Letters 22(2):901 (2012)

    VER-156084 ( 1) shows dose-dependant in vivo FAAH inhibition in an anandamide-loading study in the rat.
  8. Adenosine-derived inhibitors of 78 kDa glucose regulated protein (Grp78) ATPase: insights into isoform selectivity.

    Journal of medicinal and pharmaceutical chemistry 54(12):4034 (2011) PMID 21526763

    78 kDa glucose-regulated protein (Grp78) is a heat shock protein (HSP) involved in protein folding that plays a role in cancer cell proliferation. Binding of adenosine-derived inhibitors to Grp78 was characterized by surface plasmon resonance and isothermal titration calorimetry. The most potent...
  9. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells.

    Cancer Chemotherapy and Pharmacology 66(3):535 (2010) PMID 20012863

    The anti-apoptotic function of the 70 kDa family of heat shock proteins and their role in cancer is well documented. Dual targeting of Hsc70 and Hsp70 with siRNA induces proteasome-dependent degradation of Hsp90 client proteins and extensive tumor specific apoptosis as well as the potentiation o...
  10. Structure-guided design of alpha-amino acid-derived Pin1 inhibitors.

    Bioorganic & Medicinal Chemistry Letters 20(2):586 (2010) PMID 19969456

    The peptidyl prolyl cis/trans isomerase Pin1 is a promising molecular target for anti-cancer therapeutics. Here we report the structure-guided evolution of an indole 2-carboxylic acid fragment hit into a series of alpha-benzimidazolyl-substituted amino acids. Examples inhibited Pin1 activity wit...
  11. Structure-guided design of α-amino acid-derived Pin1 inhibitors

    Bioorganic & Medicinal Chemistry Letters 20(2):586 (2010)

    An indole 2-carboxylic acid fragment was evolved into a series of potent (<200 nM) α-benzimidazolyl-substituted amino acid inhibitors of the Pin1 PPIase via structure-based drug design.
  12. Corrigendum to “Structure-guided design of α-amino acid-derived Pin1 inhibitors” [Bioorg. Med. Chem. Lett. 20 (2010) 586]

    Bioorganic & Medicinal Chemistry Letters 20(16):e1 (2010)

  13. Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas

    Bioorganic & Medicinal Chemistry Letters 19(15):4241 (2009)

  14. Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas.

    Bioorganic & Medicinal Chemistry Letters 19(15):4241 (2009) PMID 19515560

    We report the discovery of a novel, chiral azetidine urea inhibitor of Fatty Acid Amide Hydrolase (FAAH,) and describe the surprising species selectivity of VER-156084 versus rat and human FAAH and also hCB1.
  15. Towards the discovery of drug-like RNA ligands?

    Drug Discovery Today 11(21-22):1019 (2006) PMID 17055412

    Targeting RNA with small molecule drugs is an area of great potential for therapeutic treatment of infections and possibly genetic and autoimmune diseases. However, a mature set of precedents and established methodology is lacking. The physicochemical properties of RNA raise specific issues and ...
  16. Towards the discovery of drug-like RNA ligands?

    Drug Discovery Today 11(21):1019 (2006)

    Targeting RNA with small molecule drugs is an area of great potential for therapeutic treatment of infections and possibly genetic and autoimmune diseases. However, a mature set of precedents and established methodology is lacking. The physicochemical properties of RNA raise specific issues...
  17. Structure-based design of agents targeting the bacterial ribosome.

    Bioorganic & Medicinal Chemistry Letters 13(15):2455 (2003) PMID 12852942

    Rational structure-based drug design has been applied to the antibiotic thiostrepton, in an attempt to overcome some of its' limitations. The identification of a proposed binding fragment allowed construction of a number of key fragments, which were derivatised to generate a library of potential...
  18. Structural basis for contrasting activities of ribosome binding thiazole antibiotics.

    Chemistry & Biology 10(8):769 (2003) PMID 12954336

    Thiostrepton and micrococcin inhibit protein synthesis by binding to the L11 binding domain (L11BD) of 23S ribosomal RNA. The two compounds are structurally related, yet they produce different effects on ribosomal RNA in footprinting experiments and on elongation factor-G (EF-G)-dependent GTP hy...
  19. Structural Basis for Contrasting Activities of Ribosome Binding Thiazole Antibiotics

    Chemistry & Biology 10(8):769 (2003)

    Thiostrepton and micrococcin inhibit protein synthesis by binding to the L11 binding domain (L11BD) of 23S ribosomal RNA. The two compounds are structurally related, yet they produce different effects on ribosomal RNA in footprinting experiments and on elongation factor-G (EF-G)-dependent G...
  20. Structure-based design of agents targeting the bacterial ribosome

    Bioorganic & Medicinal Chemistry Letters 13(15):2455 (2003)

    Rational structure-based drug design has been applied to the antibiotic thiostrepton, in an attempt to overcome some of its’ limitations. The identification of a proposed binding fragment allowed construction of a number of key fragments, which were derivatised to generate a library of pote...