The C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells

Abstract

N-terminal HSP90 inhibitors in development have had issues arising from heat shock response (HSR) induction and off-target effects. We sought to investigate the capacity of NCT-58, a rationally-synthesized C-terminal HSP90 inhibitor, to kill trastuzumab-resistant HER2-positive breast cancer stem-like cells. NCT-58 does not induce the HSR due to its targeting of the C-terminal region and elicits anti-tumor activity via the simultaneous downregulation of HER family members as well as inhibition of Akt phosphorylation. NCT-58 kills the rapidly proliferating bulk tumor cells as well as the breast cancer stem-like population, coinciding with significant reductions in stem/progenitor markers and pluripotent transcription factors. NCT-58 treatment suppressed growth and angiogenesis in a trastuzumab-resistant xenograft model, concomitant with downregulation of ICD-HER2 and HSF-1/HSP70/HSP90. These findings warrant further investigation of NCT-58 to address trastuzumab resistance in heterogeneous HER2-positive cancers.

β-Escin overcomes trastuzumab resistance in HER2-positive breast cancer by targeting cancer stem-like features

“…Mammospheres harbor plentiful mammary stem-like cells and the sphere formation assay is an efficient tool for evaluating the effect of CSC targeting drugs [ 31 ]. We have previously reported that stemness-related proteins including ALDH1, Nanog, Oct4, and Sox2 were higher in mammospheres compared to their adherent counterparts [ 32 ]. Formation of mammospheres derived from BT474 and JIMT-1 cells was markedly attenuated in response to β-escin treatment (10-20 μM), as evidenced by a significant decrease in the number and volume of mammosphere formed under anchorage-independent serum-free culture conditions (*** p <0.001, Fig.…”

“…The mesenchymal-like CD44 high /CD24 low population is an aggressive phenotype, that is highly tumorigenic and more resistant to drugs [ 28 ]. The CD44 high /CD24 low phenotypes account for approximately 0.5% of trastuzumab-sensitive BT474 cells, whereas they account for more than 50% in trastuzumab-resistant JIMT-1 cells [ 32 , 33 ]. In the present study, the CD44 high /CD24 low subpopulations of JIMT-1 cells were as high as 63.4%, and these cell populations were significantly reduced by β-escin challenge (*** p <0.001, Fig.…”

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

“…13 C NMR (125 MHz, CDCl 3 ) δ 186.9, 161.0 (×2), 152.1, 138.9, 137.8, 128.9, 105.9 (×2), 101.9, 96.1, 55. 5 1E,4E)-1-(Benzoijd]ij1,3]dioxol-4-yl)-5-(methylamino)penta-1,4-dien-3-one (1q) (20% yield); yellow oil. 1 H NMR (600 MHz, CDCl 3 ) δ 10.24 (s, 1H), 7.42 (d, J = 15.9 Hz, 1H), 6.94 (dd, J = 7.9, 0.9 Hz, 1H), 6.88 (d, J = 15.9 Hz, 1H), 6.84 (dd, J = 12.7, 7.2 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.77 (dd, J = 7.7, 1.1 Hz, 1H), 6.04 (s, 2H), 5.20 (d, J = 7.1 Hz, 1H), 3.06 (d, J = 4.9 Hz, 3H).…”

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

“…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.…”