Russell A. Judge

Abbott Laboratories, North Chicago, Illinois, United States

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Publications (53)116.34 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization.
    ACS Medicinal Chemistry Letters 08/2014; · 3.07 Impact Factor
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    ABSTRACT: Abstract In the present study, we report the structure of the free and drug-bound Fab fragment of a high affinity anti-methotrexate antibody and perform a thermodynamic analysis of the binding process. The anti-methotrexate Fab fragment features a remarkably rigid tunnel-like binding site that extends into a water channel serving as the specialized route to move solvent out and into the site upon ligand binding and dissociation. This new finding in antibody structure-function relationships directly relates to the fast association (1107 M-1s-1) and slow (410-5 s-1) dissociation rates determined for mAb ADD056, resulting in a very strong binding with a KD ~ 3.6 pM at 20°C. As follows from the X-ray data analysis, the methotrexate-antibody complex is stabilized by an extended network of hydrogen bonds and stacking interactions. The analysis also shows structural involvement of the CDR H3 in formation of the water channel revealing another important role of this hypervariable region, which suggests a new direction in natural affinity maturation and opens a new possibility in antibody engineering. Methotrexate is a widely used therapeutic agent for many malignant diseases and inflammatory disorders. Unfortunately, it may also interfere with central aspects of metabolism and thereby cause inevitable side effects. Therefore, methotrexate therapy requires careful monitoring of drug blood levels, which is traditionally done by immunoassays. An understanding of the structure-function properties of antibodies selected for drug monitoring substantiates the performance and robustness of such tests.
    Biochemistry 05/2014; · 3.38 Impact Factor
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    ABSTRACT: Ketol-isomerases catalyze the reversible isomerization between aldoses and ketoses. D-Xylose isomerase carries out the first reaction in the catabolism of D-xylose, but is also able to convert D-glucose to D-fructose. The first step of the reaction is an enzyme-catalyzed ring opening of the cyclic substrate. The active-site amino-acid acid/base pair involved in ring opening has long been investigated and several models have been proposed. Here, the structure of the xylose isomerase E186Q mutant with cyclic glucose bound at the active site, refined against joint X-ray and neutron diffraction data, is reported. Detailed analysis of the hydrogen-bond networks at the active site of the enzyme suggests that His54, which is doubly protonated, is poised to protonate the glucose O5 position, while Lys289, which is neutral, promotes deprotonation of the glucose O1H hydroxyl group via an activated water molecule. The structure also reveals an extended hydrogen-bonding network that connects the conserved residues Lys289 and Lys183 through three structurally conserved water molecules and residue 186, which is a glutamic acid to glutamine mutation.
    Acta Crystallographica Section D Biological Crystallography 02/2014; 70(Pt 2):414-420. · 7.23 Impact Factor
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    ABSTRACT: Successfully forming ligand-protein complexes with specific compounds can be a significant challenge in supporting structure-based drug design for a given protein target. In this respect, an on-column ligand- and detergent-exchange method was developed to obtain ligand-protein complexes of an adamantane series of compounds with 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) after a variety of other complexation methods had failed. This report describes the on-column exchange method and an unexpected byproduct of the method in which artificial trimers were observed in the structures.
    Acta Crystallographica Section F Structural Biology and Crystallization Communications 05/2012; 68(Pt 5):601-5. · 0.57 Impact Factor
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    ABSTRACT: We describe the development of a novel series of N-aryl-benzimidazolone HSP90 inhibitors (9) targeting the N-terminal ATP-ase site. SAR development was influenced by structure-based design based around X-ray structures of ligand bound HSP90 complexes. Lead compounds exhibited high binding affinities, ATP-ase inhibition and cellular client protein degradation.
    Bioorganic & medicinal chemistry letters 12/2010; 20(24):7503-6. · 2.65 Impact Factor
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    ABSTRACT: Like many small molecule materials, tetragonal lysozyme crystals exhibit growth rate dispersion. To investigate this phenomenon further, the growth rate dispersion of the (110) and (101) crystal faces was determined as a function of sodium chloride concentration, temperature, and solution pH. Under the conditions investigated, the growth rate dispersion follows the constant crystal growth model, in which each individual crystal is assumed to have a unique, constant growth rate. While the growth rate dispersion of the (110) face seems independent of the solution conditions, for the (101) face it was observed to vary systematically with temperature and pH. The greater susceptibility of the (101) face to the causes of growth rate dispersion was interpreted in light of a model proposed to explain the differing growth mechanisms of each face. Overall, the magnitude of crystal growth rate dispersion observed for lysozyme is similar to that reported for some small organic molecules.
    Crystal Growth & Design 06/2010; 10(7). · 4.56 Impact Factor
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    ABSTRACT: Ionic liquids exhibit a variety of properties that make them attractive solvents for biomaterials. Given the potential for productive interaction between ionic liquids and biological macromolecules, we investigated the use of ionic liquids as precipitating agents and additives for protein crystallization for six model proteins (lysozyme, catalase, myoglobin, trypsin, glucose isomerase, and xylanase). The ionic liquids produced changes in crystal morphology and mediated significant increases in crystal size in some cases. Crystals grown using ionic liquids as precipitating agents or as additives provided X-ray diffraction resolution similar to or better than that obtained without ionic liquids. Based upon the experiments performed with model proteins, the ionic liquids were used as additives for the crystallization of the poorly diffracting monoclonal antibody 106.3 Fab in complex with the B-type natriuretic peptide (5-13). The ionic liquids improved the crystallization behavior and provided improved diffraction resulting in the determination of the structure. Ionic liquids should be considered as useful additives for the crystallization of other proteins.
    Crystal Growth & Design 08/2009; 9(8). · 4.56 Impact Factor
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    ABSTRACT: Texas Red dyes were used to partially label proteins for crystallization in both detergent and lipidic meso-phases. Fluorescence detection of Texas Red can then be used to differentiate the protein crystals from salt crystals and other phase separations in the crystallization drop. Whereas ultraviolet light absorption and fluorescence of protein crystals in lipidic meso phase crystallization trials using glass sandwich plates was difficult to discern, the fluorescence of the partially labeled protein can be used to distinguish protein crystals. With as little as 0.05% Texas Red labeling of the protein, protein crystals showed up very clearly in both detergent and the lipid meso-phase crystallization setups.
    The Open Structural Biology Journal 02/2009; 309(11):11-15.
  • Russell A. Judge
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    ABSTRACT: The challenge in supporting biological macromolecule crystallization projects for structure based drug design is to develop robust crystallization systems, from which high-resolution crystal structures for a variety of ligand complexes can be obtained. Each biological macromolecule is unique, often requiring the testing of binding partners, additives, purification tag placement and crystallization methods, in addition to solution condition screening. It is often a combination of a number of these factors that lead to the most robust crystallization system. In this presentation we will discuss case studies illustrating how the use of additives such as ionic liquids, second site binders, crystallization method, tag placement and purification methods have provided high quality crystals for a number of biological macromolecules.
    2008 AIChE Annual Meeting; 11/2008
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    ABSTRACT: The molecular chaperone HSP90 has been shown to facilitate cancer cell survival by stabilizing key proteins responsible for a malignant phenotype. We report here the results of parallel fragment-based drug design approaches in the design of novel HSP90 inhibitors. Initial aminopyrimidine leads were elaborated using high-throughput organic synthesis to yield nanomolar inhibitors of the enzyme. Second site leads were also identified which bound to HSP90 in two distinct conformations, an 'open' and 'closed' form. Intriguingly, linked fragment approaches targeting both of these conformations were successful in producing novel, micromolar inhibitors. Overall, this study shows that, with only a few fragment hits, multiple lead series can be generated for HSP90 due to the inherent flexibility of the active site. Thus, ample opportunities exist to use these lead series in the development of clinically useful HSP90 inhibitors for the treatment of cancers.
    Chemical Biology &amp Drug Design 08/2007; 70(1):1-12. · 2.51 Impact Factor
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    ABSTRACT: A series of aryl sulfonamides of 5,6-disubstituted anthranilic acids were identified as potent inhibitors of methionine aminopeptidase-2 (MetAP2). Small alkyl groups and 3-furyl were tolerated at the 5-position of anthranilic acid, while -OCH(3), CH(3), and Cl were found optimal for the 6-position. Placement of 2-aminoethoxy group at the 6-position enabled interaction with the second Mn(2+) but did not result in enhancement in potency. Introduction of a tertiary amino moiety at the ortho-position of the sulfonyl phenyl ring gave reduced protein binding and improved cellular activity, but led to lower oral bioavailability.
    Bioorganic & Medicinal Chemistry Letters 06/2007; 17(10):2817-22. · 2.33 Impact Factor
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    ABSTRACT: Based on the crystallographic analysis of a urea-checkpoint kinase 1 (Chk1) complex and molecular modeling, a class of macrocyclic Chk1 inhibitors were designed and their biological activities were evaluated. An efficient synthetic methodology for macrocyclic ureas was developed with Grubbs metathesis macrocyclization as the key step. The structure-activity relationship studies demonstrated that the macrocyclization retains full Chk1 inhibition activity and that the 4-position of the phenyl ring can tolerate a wide variety of substituents. These novel Chk1 inhibitors exhibit excellent selectivity over a panel of more than 70 kinases. Compounds 5b, 5c, 5f, 15, 16d, 17g, 17h, 17k, 18d, and 22 were identified as ideal Chk1 inhibitors, which showed little or no single-agent activity but significantly potentiate the cytotoxicities of the DNA-damaging antitumor agents doxorubicin and camptothecin. These novel Chk1 inhibitors abrogate the doxorubicin-induced G2 and camptothecin-induced S checkpoint arrests, confirming that their potent biological activities are mechanism-based through Chk1 inhibition.
    Journal of Medicinal Chemistry 05/2007; 50(7):1514-27. · 5.48 Impact Factor
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    ABSTRACT: A new class of checkpoint kinase 1 (CHK-1) inhibitors bearing a 1,4-dihydroindeno[1,2-c]pyrazole core was developed after initial hits from high throughput screening. The efficient hit-to-lead process was facilitated by X-ray crystallography and led to potent inhibitors (<10nM) against CHK-1. X-ray co-crystal structures of bound inhibitors demonstrated that two sub-series of this class of compounds, exemplified by 21 and 41, exhibit distinctive hydrogen bonding patterns in the specificity pocket of the active site. Two compounds, 41 and 43, were capable of potentiating doxorubicin and camptothecin, both DNA-damaging agents, in cell proliferation assays (MTS and soft agar assays) and abrogating G2/M checkpoint in a mechanism-based FACS assay.
    Bioorganic & Medicinal Chemistry 05/2007; 15(7):2759-67. · 2.95 Impact Factor
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    ABSTRACT: A novel class of adamantane ethers 11beta-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynamic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed.
    Bioorganic & Medicinal Chemistry Letters 03/2007; 17(3):750-5. · 2.33 Impact Factor
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    ABSTRACT: Potent and selective adamantane sulfone and sulfonamide inhibitors of 11-beta-HSD-1 have been discovered. Selected compounds from these series have robust pharmacokinetic profiles and strongly inhibit liver, fat, and brain HSD1 for extended periods after oral dosing.
    Bioorganic & Medicinal Chemistry Letters 02/2007; 17(2):527-32. · 2.33 Impact Factor
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    ABSTRACT: Kinase enzymes are involved in a vast array of biological processes associated with human disease; therefore, selective kinase inhibition by small molecules and therapeutic antibodies is an area of intense study. The authors show that drug candidates with immediate value for biological preclinical evaluation can be identified directly through ultra-efficient affinity screening of kinase enzymes and random compound mixtures. The screening process comprises sampling and trapping equilibrium binding between candidate ligands and protein in solution, followed by removal of unbound ligands via 3 rounds of ultrafiltration and direct identification of bound ligands by mass spectrometry. Evaluation of significant peaks is facilitated by automated integration and collation of the mass spectral data and import into custom software for analysis. One Chk1-selective ligand found by using this process is presented in detail. The compound is potent in both enzymatic and Chk1-dependent cellular assays, and specific contacts in the Chk1 active site are shown by X-ray crystallography.
    Journal of Biomolecular Screening 11/2006; 11(7):755-64. · 2.01 Impact Factor
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    ABSTRACT: Neutron diffraction is uniquely sensitive to hydrogen positions and protonation state. In that context structural information from neutron data is complementary to that provided through X-ray diffraction. However, there are practical obstacles to overcome in fully exploiting the potential of neutron diffraction, i.e. low flux and weak scattering. Several approaches are available to overcome these obstacles and we have investigated the simplest: increasing the diffracting volume of the crystals. Volume is a quantifiable metric that is well suited for experimental design and optimization techniques. By using response surface methods we have optimized the xylose isomerase crystal volume, enabling neutron diffraction while we determined the crystallization parameters with a minimum of experiments. Our results suggest a systematic means of enabling neutron diffraction studies for a larger number of samples that require information on hydrogen position and/or protonation state.
    European Biophysics Journal 10/2006; 35(7):621-32. · 2.47 Impact Factor
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    ABSTRACT: The location of hydrogen atoms in enzyme structures can bring critical understanding of catalytic mechanism. However, whilst it is often difficult to determine the position of hydrogen atoms using X-ray crystallography even with subatomic (<1.0 A) resolution data available, neutron crystallography provides an experimental tool to directly localize hydrogen/deuterium atoms in biological macromolecules at resolution of 1.5-2.0 A. D-Xylose isomerase (D-xylose ketol-isomerase, EC is a 43 kDa enzyme that catalyses the first reaction in the catabolism of D-xylose. Linearization and isomerization of D-xylose at the active site of D-xylose isomerase rely upon a complex hydrogen transfer. Neutron quasi-Laue data at 2.2 A resolution were collected at room temperature on a partially deuterated Streptomyces rubiginosus D-xylose isomerase crystal using the LADI instrument at ILL with the objective to provide insight into the enzymatic mechanism. The neutron structure shows unambiguously that residue His 53 is doubly protonated at the active site of the enzyme. This suggests that the reaction proceeds through an acid catalyzed opening of the sugar ring, which is in accord with the mechanism suggested by Fenn et al. (Biochemistry 43(21): 6464-6474, 2004). This is the first report of direct observation of double protonation of His 53 and the first validation of the ring opening mechanism at the active site of D-xylose isomerase.
    European Biophysics Journal 09/2006; 35(7):601-9. · 2.47 Impact Factor
  • Martina N Carbone, Russell A Judge, Mark R Etzel
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    ABSTRACT: Bulk protein crystallization, unlike small molecule crystallization, has found very limited use in biopharmaceutical manufacture. Most work in this area targets obtaining single large crystals for molecular structure determination by crystallography. Design and optimization of bulk crystallization for protein recovery and purification is much less common, and requires a mathematical model for analysis of laboratory data suitable for scale-up purposes. Traditionally, the crystal size distribution and method of moments is used to characterize the crystallization process. A simpler method is presented in this paper that utilizes the desupersaturation curve. The method uses an approach that does not require expensive instrumentation or characterization of the seed crystal size distribution. The method is extended to allow determination of both the mass deposition rate constant and the growth rate order from a single desuperaturation curve. Experimental data for the bulk crystallization of ovalbumin are used to validate the method. The rate constants and rate order obtained using the new method compare well with literature values. Scale-up is illustrated by prediction of the impact of changes in seed mass on protein crystallization. This new method offers a straightforward and low-cost alternative to traditional methods for the analysis and scale-up of protein crystallization data.
    Biotechnology and Bioengineering 08/2005; 91(1):84-90. · 4.16 Impact Factor
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    ABSTRACT: Since the 1980s hundreds of macromolecular crystal growth experiments have been performed in the reduced acceleration environment of an orbiting spacecraft. Significant enhancements in structural knowledge have resulted from X-ray diffraction of the crystals grown. Similarly, many samples have shown no improvement or degradation in comparison to those grown on the ground. A complex series of interrelated factors affect these experiments and by building a comprehensive archive of the results it was aimed to identify factors that result in success and those that result in failure. Specifically, it was found that dedicated microgravity missions increase the chance of success when compared with those where crystallization took place as a parasitic aspect of the mission. It was also found that the chance of success could not be predicted based on any discernible property of the macromolecule available to us.
    Acta Crystallographica Section D Biological Crystallography 07/2005; 61(Pt 6):763-71. · 7.23 Impact Factor

Publication Stats

507 Citations
116.34 Total Impact Points


  • 2005–2008
    • Abbott Laboratories
      • Abbott Laboratories
      North Chicago, Illinois, United States
  • 2001
    • University of Alabama in Huntsville
      Huntsville, Alabama, United States
    • NASA
      Washington, West Virginia, United States
  • 1995
    • University of Queensland
      • School of Chemical Engineering
      Brisbane, Queensland, Australia