Structure-Activity Relationships of Benzothiazole-Based Hsp90 C-Terminal-Domain Inhibitors

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.

Catalytic Stereoconvergent Synthesis of Homochiral β-CF3, β-SCF3, and β-OCF3 Benzylic Alcohols

“…Compound 10 was designed using a molecular-dynamics-derived pharmacophore model (Figure S2). 110,111 It was shown to inhibit Hsp90 in the luciferase refolding assay and display antiproliferative activity in the SkBr3 breast cancer cell line (IC 50 = 51 ± 2 μM).…”

Targeting HSP90 with picropodophyllin suppresses gastric cancer tumorigenesis by disrupting the association of HSP90 and AKT

“…To date, no HSP90 inhibitor has been approved for cancer therapeutics. The primary obstacles preventing the clinical application of HSP90 inhibitors are the lack of drug‐like properties, organ toxicity, and drug resistance (Dernovšek & Tomašič, 2023). In this study, in vivo experiments showed that PPP exerts no toxicity on the primary organs of mice, thereby suggesting its potential as a natural and safe inhibitor of HSP90.…”

In Silico Discovery and Optimisation of a Novel Structural Class of Hsp90 C-Terminal Domain Inhibitors

“…Representative structures of Hsp90 CTD inhibitors; novobiocin and analogues (1-3) [28,29], deguelin and analogues (4-6) [31,33], silybin (7), EGCG (8) and a benzothiazole-based inhibitor (9) [37].…”

“…Although the potency of Hsp90 CTD inhibitors has improved significantly compared to novobiocin, the scaffold diversity is still scarce. Known inhibitors include novobiocin analogues, analogues of other natural products such as deguelin, EGCG, silybin and scaffolds already established as inhibitors of other targets, e.g., benzothiazole-based DNA gyrase B inhibitors ( 4–9 , Figure 1 ) [ 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. To expand the structural diversity of Hsp90 CTD inhibitors, we performed structure-based virtual screening to discover novel scaffolds.…”

“…We discovered a new structural class of Hsp90 CTD inhibitors bearing a substituted aromatic ring and a basic amine at the required distance based on the observed structure-activity relationships and our pharmacophore models. Moreover, we have successfully used the pharmacophore model to optimise the benzothiazole class of Hsp90 CTD inhibitors [ 37 ].…”