Tricyclic Series of Heat Shock Protein 90 (Hsp90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-c]pyridines as Potent Inhibitors of the Hsp90 Molecular Chaperone

Abstract

A novel class of heat shock protein 90 (Hsp90) inhibitors was developed after a low throughput screen (LTS) of a focused library containing approximately 21K compounds selected by virtual screening. The initial [1-{3-H-imidazo[4-5-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole-6-one] (1) compound showed moderate activity (IC(50) = 7.6 μM on Hsp82, the yeast homologue of Hsp90). A high-resolution X-ray structure shows that compound 1 binds into an "induced" hydrophobic pocket, 10-15 Å away from the ATP/resorcinol binding site. Iterative cycles of structure-based drug design (SBDD) and chemical synthesis led to the design and preparation of analogues with improved affinity. These optimized molecules make productive interactions within the ATP binding site as reported by other Hsp90 inhibitors. This resulted in compound 8, which is a highly potent inhibitor in biochemical and cellular assays (K(d) = 0.35 nM on Hsp90; IC(50) = 30 nM on SKBr3 mammary carcinoma cells) and in an in vivo leukemia model.

Differences in Conformational Dynamics between Plasmodium falciparum and Human Hsp90 Orthologues Enable the Structure-Based Discovery of Pathogen-Selective Inhibitors

“…6,24 Strongly driven by the potential to treat cancer with Hsp90 inhibitors, the development of such inhibitors has rapidly progressed in the last years and there currently exists a broad range of pharmacophores ranging from natural ansamycins to synthetic derivatives of purine, resorcinol, benzamide, aminopyri(mi)dines, and tricyclic imidazopyridines. 9,25,26 In contrast, the development of species-specific Hsp90 inhibitors is still in its infancy. We previously presented a living test system based on the growth of a panel of isogenic yeast strains, each living on Hsp90 from a different species.…”

Structure insights into mechanisms of ATP hydrolysis and the activation of human heat-shock protein 90

“…Shiau et al [7] described the cryo-electron microscopy as well as X-ray structures of nucleotide-free, AMPPNP-bound, and ADP-bound states of HtpG (Escherichia coli Hsp90 ortholog), which were similar in both size and detailed shape to the yeast Hsp90-AMPPNP structure. In addition, a series of X-ray crystal structures of human Hsp90 N inhibitors have been reported [13][14][15]. Although the structures of the isolated N-terminus of human Hsp90 and the protein in complex with ATPgS have been reported [11,16], it is still not clear as to how Hsp90 catalytically hydrolyzes ATP to produce ADP at the atomic level.…”

Establish an automated flow injection ESI-MS method for the screening of fragment based libraries: Application to Hsp90

“…The use of ESI-MS to investigate this target was previously reported by Vallée and coworkers in the medicinal chemistry optimization of tricyclic imidazo [4,5-c]pyridines as a new class of Hsp90 inhibitors (Vallee et al, 2011).…”