Publications (5)15.28 Total impact
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Article: Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of Polo-like kinase 1 (MLN0905).
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ABSTRACT: This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.Journal of Medicinal Chemistry 11/2011; 55(1):197-208. · 4.80 Impact Factor -
Article: Characterization of a new series of non-covalent proteasome inhibitors with exquisite potency and selectivity for the 20S beta5-subunit.
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ABSTRACT: The mammalian 26S proteasome is a 2500 kDa multi-catalytic complex involved in intracellular protein degradation. We describe the synthesis and properties of a novel series of non-covalent di-peptide inhibitors of the proteasome based [corrected] on a capped tri-peptide that was first identified by high-throughput screening of a library of approx. 350000 compounds for inhibitors of the ubiquitin-proteasome system in cells. We show that these compounds are entirely selective for the beta5 (chymotrypsin-like) site over the beta1 (caspase-like) and beta2 (trypsin-like) sites of the 20S core particle of the proteasome, and over a panel of less closely related proteases. Compound optimization, guided by X-ray crystallography of the liganded 20S core particle, confirmed their non-covalent binding mode and provided a structural basis for their enhanced in vitro and cellular potencies. We demonstrate that such compounds show low nanomolar IC50 values for the human 20S beta5 site in vitro, and that pharmacological inhibition of this site in cells is sufficient to potently inhibit the degradation of a tetra-ubiquitin-luciferase reporter, activation of NFkappaB (nuclear factor kappaB) in response to TNF-alpha (tumour necrosis factor-alpha) and the proliferation of cancer cells. Finally, we identified capped di-peptides that show differential selectivity for the beta5 site of the constitutively expressed proteasome and immunoproteasome in vitro and in B-cell lymphomas. Collectively, these studies describe the synthesis, activity and binding mode of a new series of non-covalent proteasome inhibitors with unprecedented potency and selectivity for the beta5 site, and which can discriminate between the constitutive proteasome and immunoproteasome in vitro and in cells.Biochemical Journal 09/2010; 430(3):461-76. · 4.90 Impact Factor -
Article: Optimization of a series of dipeptides with a P3 threonine residue as non-covalent inhibitors of the chymotrypsin-like activity of the human 20S proteasome.
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ABSTRACT: Starting from a tripeptide screening hit, a series of dipeptide inhibitors of the proteasome with Thr as the P3 residue has been optimized with the aid of crystal structures in complex with the β-5/6 active site of y20S. Derivative 25, (β5 IC(50)=7.4 nM) inhibits only the chymotryptic activity of the proteasome, shows cellular activity against targets in the UPS, and inhibits proliferation.Bioorganic & medicinal chemistry letters 09/2010; 20(22):6581-6. · 2.65 Impact Factor -
Article: Configuration of a scintillation proximity assay for the activity assessment of recombinant human adenine phosphoribosyltransferase.
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ABSTRACT: Adenine phosphoribosyltransferase plays a role in purine salvage by catalyzing the direct conversion of adenine to adenosine monophosphate. The involvement of the purine salvage pathway in tumor proliferation and angiogenesis makes adenine phosphoribosyltransferase a potential target for oncology drug discovery. We have expressed and characterized recombinant, N-terminally His-tagged human adenine phosphoribosyltransferase. Two assay formats were assessed for use in a high throughput screen: a spectrophotometric-based enzyme-coupled assay system and a radiometric ionic capture scintillation proximity bead assay format. Ultimately, the scintillation proximity assay format was chosen because of automated screening compatibility limitations of the coupled assay. We describe here the biochemical characterization of adenine phosphoribosyltransferase and the development of a robust, homogeneous, 384-well assay suitable for high throughput screening.Assay and Drug Development Technologies 01/2007; 4(6):661-9. · 1.73 Impact Factor -
Article: pH Dependence of inhibitors targeting the occluding loop of cathepsin B.
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ABSTRACT: Potent and selective cathepsin B inhibitors have previously been synthesized based upon the natural product cysteine protease inhibitor E-64. X-ray crystal data indicates that these compounds interact through their free carboxylate with the positively charged histidine residues located on the prime-side of the active site within the occluding loop of cathepsin B. Herein, we examine the pH dependence of two prime-side-binding compounds. In each case there is a dramatic decrease in k(inact)/K(I) as the pH is raised from 4 to 7.8 corresponding to a single ionization of pK(a) 4.4. These results suggest that targeting of the occluding loop of cathepsin B may be a poor inhibitor design strategy if the enzyme environment has a pH greater than 5.5. However, this type of inhibitor may be a useful tool to help elucidate the role and the environment of cathepsin B in invading tumors.Bioorganic Chemistry 09/2002; 30(4):264-75. · 1.21 Impact Factor
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2007
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Millennium Pharmaceuticals Inc
Boston, MA, USA
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