Recent advances toward the development of Hsp90 C-terminal inhibitors

A silicon-containing aryl/penta-1,4-dien-3-one/amine hybrid exhibits antiproliferative effects on breast cancer cells by targeting the HSP90 C-terminus without inducing heat-shock response

“…Inspired by previously published HSP90 C-terminal inhibitors (Fig. 1), the aryl groups (like the green parts in curcumin, 44 SH-1242, carboxamide, EGCG, and others 10 ), the α,β-unsaturated ketone fragments (like the red parts in curcumin, vibsanin B, VB4157, and others 10 ), and the tertiary amines (like the blue parts in VB4157, carboxamide, and others 10 ) are key pharmacophores and frequently presented. We envisioned that a new scaffold for HSP90 C-terminal inhibitors might be readily obtained through the combination of these key fragments.…”

“…7 Geldanamycin-, radicicol-, and novobiocin-based derivatives are representative examples of HSP90 inhibitors that have shown high potential in treating various subtypes of breast cancer, and some are already undergoing clinical studies. [8][9][10][11][12][13] A range of structurally designed HSP90 inhibitors with remarkable properties have been reported during the past two decades. Notably, HSP90 C-terminal and HSP90 isoformselective inhibitors have emerged as current hotspots for HSP90 inhibitors due to their outstanding functions in molecular biology.…”

“…Notably, HSP90 C-terminal and HSP90 isoformselective inhibitors have emerged as current hotspots for HSP90 inhibitors due to their outstanding functions in molecular biology. 10,11,14 These inhibitors have exhibited potent antiproliferative activity against various breast cancer cell lines. Blagg et al carried out a landmark medicinal chemistry on the natural product novobiocin and systematically developed various novobiocin-based HSP90 C-terminal inhibitors that exhibited a great potency towards HER2-positive breast cancer.…”

“…7 Geldanamycin-, radicicol-, and novobiocin-based derivatives are representative examples of HSP90 inhibitors that have shown high potential in treating various subtypes of breast cancer, and some are already undergoing clinical studies. 8–13…”

Enniatin A Analogues as Novel Hsp90 Inhibitors that Modulate Triple-Negative Breast Cancer

“…Unfortunately, most of these molecules failed due to cardiac and ocular toxicities, as well as dose-escalating toxicities, associated with pan -inhibition of all four Hsp90 isoforms that results in induction of the pro-survival heat shock response (HSR), which includes the overexpression of Hsp90. , Therefore, a need exists for inhibitors that can provide an alternative mechanism of action. Several approaches are currently being explored to minimize the deleterious consequences that result from pan -Hsp90 inhibition and include C-terminal inhibition, − disruption of Hsp90 C-terminal dimerization, isoform-selective inhibition, − and disruption of Hsp90 protein–protein interactions (PPIs) between client substrates and/or cochaperones …”