1. 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...
  2. 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...
  3. 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...
  4. Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution

    Bioorganic & Medicinal Chemistry Letters 20(22):6483 (2010) PMID 20932746

    Structure-guided techniques were used to evolve a 5-pyridinyl pyrazole-3-carboxylate fragment into a series of 5-aryl-carbamoyl-3-phenyl-imidazole-4-carboxylates, examples of which inhibited the Pin1 PPIase with sub-μM IC 50 and blocked proliferation of prostate cancer cells.
  5. Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution

    Bioorganic & Medicinal Chemistry Letters 20(22):6483 (2010) PMID 20932746

    Structure-guided techniques were used to evolve a 5-pyridinyl pyrazole-3-carboxylate fragment into a series of 5-aryl-carbamoyl-3-phenyl-imidazole-4-carboxylates, examples of which inhibited the Pin1 PPIase with sub-μM IC 50 and blocked proliferation of prostate cancer cells.
  6. Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution

    Bioorganic & Medicinal Chemistry Letters 20(22):6483 (2010) PMID 20932746

    Structure-guided techniques were used to evolve a 5-pyridinyl pyrazole-3-carboxylate fragment into a series of 5-aryl-carbamoyl-3-phenyl-imidazole-4-carboxylates, examples of which inhibited the Pin1 PPIase with sub-μM IC 50 and blocked proliferation of prostate cancer cells.
  7. 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)

  8. 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.
  9. Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design.

    Journal of medicinal and pharmaceutical chemistry 52(6):1510 (2009) PMID 19256508

    The design and synthesis of novel adenosine-derived inhibitors of HSP70, guided by modeling and X-ray crystallographic structures of these compounds in complex with HSC70/BAG-1, is described. Examples exhibited submicromolar affinity for HSP70, were highly selective over HSP90, and some displaye...
  10. Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping.

    Bioorganic & Medicinal Chemistry Letters 17(14):3880 (2007) PMID 17570665

    Virtual screening against a pCDK2/cyclin A crystal structure led to the identification of a potent and novel CDK2 inhibitor, which exhibited an unusual mode of interaction with the kinase binding motif. With the aid of X-ray crystallography and modelling, a medicinal chemistry strategy was imple...
  11. Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping

    Bioorganic & Medicinal Chemistry Letters 17(14):3880 (2007)

    Virtual screening identified a potent CDK2 inhibitor with a novel binding mode.
  12. Molecular basis of AKAP specificity for PKA regulatory subunits.

    Molecular Cell 24(3):383 (2006) PMID 17081989

    Localization of cyclic AMP (cAMP)-dependent protein kinase (PKA) by A kinase-anchoring proteins (AKAPs) restricts the action of this broad specificity kinase. The high-resolution crystal structures of the docking and dimerization (D/D) domain of the RIIalpha regulatory subunit of PKA both in the...
  13. Molecular Basis of AKAP Specificity for PKA Regulatory Subunits

    Molecular Cell 24(3):383 (2006)

    Localization of cyclic AMP (cAMP)-dependent protein kinase (PKA) by A kinase-anchoring proteins (AKAPs) restricts the action of this broad specificity kinase. The high-resolution crystal structures of the docking and dimerization (D/D) domain of the RIIα regulatory subunit of PKA both ...
  14. Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: protein structure-guided design and SAR.

    Bioorganic & Medicinal Chemistry Letters 16(5):1353 (2006) PMID 16325401

    Crystallographic and modelling data, in conjunction with a medicinal chemistry template-hopping approach, led to the identification of a series of novel and potent inhibitors of human cyclin-dependent kinase 2 (CDK2), with selectivity over glycogen synthase kinase-3beta (GSK-3beta). One example ...
  15. Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: Protein structure-guided design and SAR

    Bioorganic & Medicinal Chemistry Letters 16(5):1353 (2006)

    Crystallographic and modelling data, in conjunction with a medicinal chemistry template-hopping approach, led to the identification of a series of novel and potent inhibitors of human cyclin-dependent kinase 2 (CDK2), with selectivity over glycogen synthase kinase-3β (GSK-3β). One example h...
  16. Structure-guided design of pyrazolo[1,5-a]pyrimidines as inhibitors of human cyclin-dependent kinase 2.

    Bioorganic & Medicinal Chemistry Letters 15(4):863 (2005) PMID 15686876

    The protein structure guided design of a series of pyrazolo[1,5-a]pyrimidines with high potency for human cyclin-dependent kinase 2 (CDK2) is described. Some examples were shown to inhibit the growth of human colon tumour cells, were equipotent for CDK1 and were selective against GSK-3beta and o...
  17. Structure-guided design of pyrazolo[1,5-a]pyrimidines as inhibitors of human cyclin-dependent kinase 2

    Bioorganic & Medicinal Chemistry Letters 15(4):863 (2005)

    The protein structure guided design of a series of pyrazolo[1,5- a]pyrimidines with high potency for human cyclin-dependent kinase 2 (CDK2) is described. Some examples were shown to inhibit the growth of human colon tumour cells, were equipotent for CDK1 and were selective against GSK...
  18. Structure of the AAA ATPase p97

    Molecular Cell 6(6):1473 (2000)

    p97, an abundant hexameric ATPase of the AAA family, is involved in homotypic membrane fusion. It is thought to disassemble SNARE complexes formed during the process of membrane fusion. Here, we report two structures: a crystal structure of the N-terminal and D1 ATPase domains of murine p97...
  19. Synthesis, X-ray structure and high-resolution NMR spectroscopy of methyl 3-azido-2,3-dideoxy-α-d-arabino-hexopyranoside

    Carbohydrate Research 323(1):230 (1999)

    The synthesis, crystal structure data and 1H and 13C NMR spectroscopy of methyl 3-azido-2,3-dideoxy-α- d- arabino-hexopyranoside ( 5b) is reported. This compound adopts the 4 C 1 conformation. Hydrogen-bonded molecules of 5b form hel...
  20. Conformational analysis of the first observed non-prolinecis-peptide bond occurring within the complementarity determining region (CDR) of an antibody11 Edited by J. Thornton

    Journal of Molecular Biology 284(3):549 (1998)

    An analysis has been performed on the first example of a non-proline cis-peptide bond found within a complementarity determining region (CDR) of an antibody. The bond is located in CDR 3 of the heavy chain (H3) and makes substantial interactions to a peptide from a breast tumour-asso...