Abstract
Heat shock protein 90 (Hsp90) is a chaperone responsible for the maturation of many cancer-related proteins, and is therefore an important target for the design of new anticancer agents. Several Hsp90 N-terminal domain inhibitors have been evaluated in clinical trials, but none have been approved as cancer therapies. This is partly due to induction of the heat shock response, which can be avoided using Hsp90 C-terminal-domain (CTD) inhibition. Several structural features have been shown to be useful in the design of Hsp90 CTD inhibitors, including an aromatic ring, a cationic center and the benzothiazole moiety. This study established a previously unknown link between these structural motifs. Using ligand-based design methodologies and structure-based pharmacophore models, a library of 29 benzothiazole-based Hsp90 CTD inhibitors was prepared, and their antiproliferative activities were evaluated in MCF-7 breast cancer cells. Several showed low-micromolar IC50, with the most potent being compounds 5g and 9i (IC50, 2.8 ± 0.1, 3.9 ± 0.1 μM, respectively). Based on these results, a ligand-based structure–activity relationship model was built, and molecular dynamics simulation was performed to elaborate the binding mode of compound 9i. Moreover, compound 9i showed degradation of Hsp90 client proteins and no induction of the heat shock response.
Highlights
Heat shock protein 90 (Hsp90) is a chaperone that consists of four highly conserved isoforms: inducible Hsp90α and constitutively expressed Hsp90β, mitochondrial TRAP-1, and Grp94 [1,2,3].To carry out their functions, all four Hsp90 isoforms are obligate homodimers [3]
Our aim was to prepare a focused library of benzothiazolebased Hsp90 C-terminal domain (CTD) inhibitors, and to establish the structure–activity relationships (SARs) for their Hsp90 inhibition
The benzothiazole moiety was selected as a suitable central scaffold that offers the possibility for the attachment of aromatic substituents and basic amines to positions 2 and 6, which are characteristic for Hsp90 CTD inhibitors (Figure 1)
Summary
Heat shock protein 90 (Hsp90) is a chaperone that consists of four highly conserved isoforms: inducible Hsp90α and constitutively expressed Hsp90β (both localized in the cytosol), mitochondrial TRAP-1, and Grp (localized in the endoplasmic reticulum) [1,2,3].To carry out their functions, all four Hsp isoforms are obligate homodimers [3]. Heat shock protein 90 (Hsp90) is a chaperone that consists of four highly conserved isoforms: inducible Hsp90α and constitutively expressed Hsp90β (both localized in the cytosol), mitochondrial TRAP-1, and Grp (localized in the endoplasmic reticulum) [1,2,3]. Each monomeric unit of Hsp consists of an ATP-hydrolyzing N-terminal domain (NTD), which is connected via a charged linker to the middle domain and C-terminal domain (CTD) [2,4,5] This last is responsible for dimerization [5,6], and it forms a secondary nucleotide binding pocket without ATPase activity. Hsp is vital for the functionality of more than 400 proteins [12,13], its abundance still provides a functional reserve and allows cells to function even when Hsp is downregulated [14]
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