1. 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 ...
  2. Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone.

    Journal of medicinal and pharmaceutical chemistry 52(15):4794 (2009) PMID 19610616

    Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of dist...
  3. 4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer.

    Journal of Medicinal Chemistry 51(2):196 (2008) PMID 18020435

    Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4...
  4. Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues.

    Molecular Cancer Therapeutics 6(4):1198 (2007) PMID 17431102

    Although the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used stru...
  5. 4-Amino derivatives of the Hsp90 inhibitor CCT018159.

    Bioorganic & Medicinal Chemistry Letters 16(9):2543 (2006) PMID 16480864

    Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure-activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human Hsp90. Key features of the bindin...
  6. 4-Amino derivatives of the Hsp90 inhibitor CCT018159

    Bioorganic & Medicinal Chemistry Letters 16(9):2543 (2006)

    Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 have been prepared and the observed SAR explained by X-ray co-crystallography with Human Hsp90. The most potent of the new compounds has an IC 50 of less than 600 nM against t...
  7. Structure-based discovery of a new class of Hsp90 inhibitors.

    Bioorganic & Medicinal Chemistry Letters 15(23):5187 (2005) PMID 16202589

    Docking-based virtual screening identified 1-(2-phenol)-2-naphthol compounds as a new class of Hsp90 inhibitors of low to sub-micromolar potency. Here we report the binding affinities and cellular activities of several members of this class. A high resolution crystal structure of the most potent...
  8. 3-(5-Chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as inhibitors of the Hsp90 molecular chaperone.

    Bioorganic & Medicinal Chemistry Letters 15(23):5197 (2005) PMID 16213716

    Information from X-ray crystal structures of Hsp90 inhibitors bound to the human Hsp90 molecular chaperone was used to assist in the design of 3-(5-chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as novel inhibitors of Hsp90. Accessing an extra interaction with the protein via Phe138 gave a ...
  9. Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design.

    Journal of Medicinal Chemistry 48(13):4212 (2005) PMID 15974572

    The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellu...
  10. 3-(5-chloro-2,4-dihydroxyphenyl)-Pyrazole-4-carboxamides as inhibitors of the Hsp90 molecular chaperone

    Bioorganic & Medicinal Chemistry Letters 15(23):5197 (2005)

    Structure-based drug design using information from X-ray structures of ligands bound to the molecular chaperone Hsp90 has been used to assist in the design of 3-(5-chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides, several of which can make a hydrogen bond to Phe138 of the protein, afford...
  11. Structure-based discovery of a new class of Hsp90 inhibitors

    Bioorganic & Medicinal Chemistry Letters 15(23):5187 (2005)

    Docking-based virtual screening identified 1-(2-phenol)-2-naphthol compounds as a new class of Hsp90 inhibitors of low to sub-micromolar potency. Here we report the binding affinities and cellular activities of several members of this class. A high resolution crystal structure of the most p...
  12. Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms.

    Chemistry & Biology 11(6):775 (2004) PMID 15217611

    Inhibition of the ATPase activity of the chaperone protein HSP90 is a potential strategy for treatment of cancers. We have determined structures of the HSP90alpha N-terminal domain complexed with the purine-based inhibitor, PU3, and analogs with enhanced potency both in enzyme and cell-based ass...
  13. Adenine derived inhibitors of the molecular chaperone HSP90-SAR explained through multiple X-ray structures.

    Bioorganic & Medicinal Chemistry Letters 14(2):325 (2004) PMID 14698151

    Multiple co-crystal structures of an adenine-based series of inhibitors bound to the molecular chaperone Hsp90 have been determined. These structures explain the observed SAR for previously described compounds and new compounds, which possess up to 8-fold improved potency against the isolated en...
  14. Structure-Activity Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms

    Chemistry & Biology 11(6):775 (2004)

    Inhibition of the ATPase activity of the chaperone protein HSP90 is a potential strategy for treatment of cancers. We have determined structures of the HSP90α N-terminal domain complexed with the purine-based inhibitor, PU3, and analogs with enhanced potency both in enzyme and cell-based as...
  15. Adenine derived inhibitors of the molecular chaperone HSP90—SAR explained through multiple X-ray structures

    Bioorganic & Medicinal Chemistry Letters 14(2):325 (2004)

    Multiple co-crystal structures of an adenine-based series of inhibitors bound to the molecular chaperone Hsp90 have been determined. These structures explain the observed SAR for previously described compounds and new compounds, which possess up to 8-fold improved potency against the isolat...
  16. Structure-based design of peptidomimetic antagonists of p56(lck) SH2 domain.

    Bioorganic & Medicinal Chemistry Letters 12(10):1365 (2002) PMID 11992778

    Starting from the tetrapeptide Ac-pYEEI-NHMe and using a structure-based approach, we have designed and synthesised a peptidomimetic ligand for p56(lck) SH2 domain containing a conformationally restricted replacement for the two glutamate residues. We have explored replacments for the isoleucine...
  17. Structure-based design of peptidomimetic antagonists of p56lckSH2 Domain

    Bioorganic & Medicinal Chemistry Letters 12(10):1365 (2002)

    Starting from the tetrapeptide Ac-pYEEI-NHMe and using a structure-based approach, we have designed and synthesised a peptidomimetic ligand for p56 lck SH2 domain containing a conformationally restricted replacement for the two glutamate residues. We have explored repla...