Development of a novel Hsp90 inhibitor NCT-50 as a potential anticancer agent for the treatment of non-small cell lung cancer

Scientific Reports
Seung Yeob HyunHo-Young Lee

Abstract

Despite the development of advanced therapeutic regimens such as molecular targeted therapy and immunotherapy, the 5-year survival of patients with lung cancer is still less than 20%, suggesting the need to develop additional treatment strategies. The molecular chaperone heat shock protein 90 (Hsp90) plays important roles in the maturation of oncogenic proteins and thus has been considered as an anticancer therapeutic target. Here we show the efficacy and biological mechanism of a Hsp90 inhibitor NCT-50, a novobiocin-deguelin analog hybridizing the pharmacophores of these known Hsp90 inhibitors. NCT-50 exhibited significant inhibitory effects on the viability and colony formation of non-small cell lung cancer (NSCLC) cells and those carrying resistance to chemotherapy. In contrast, NCT-50 showed minimal effects on the viability of normal cells. NCT-50 induced apoptosis in NSCLC cells, inhibited the expression and activity of several Hsp90 clients including hypoxia-inducible factor (HIF)-1α, and suppressed pro-angiogenic effects of NSCLC cells. Further biochemical and in silico studies revealed that NCT-50 downregulated Hsp90 function by interacting with the C-terminal ATP-binding pocket of Hsp90, leading to decrease in the inte...Continue Reading

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Citations

Nov 12, 2019·Cancer Cell International·Zhengbin ChaiChunyan Liu
Jun 26, 2020·Frontiers in Cell and Developmental Biology·Linda Anna Michelle KulkaHeidi Olzscha
Aug 3, 2020·Bioorganic & Medicinal Chemistry Letters·Cong-Truong NguyenJeewoo Lee

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Methods Mentioned

BETA
flow cytometry
PCR
pull-down
scraping
column chromatography

Software Mentioned

GraphPad
Dock
- Dock
Sybyl
Graphpad Prism
Dox
ORCHESTRAR
Surflex

Related Concepts

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

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