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

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 interaction with Hsp90 client proteins. These results suggest the potential of NCT-50 as an anticancer Hsp90 inhibitor.

PADI3 plays an antitumor role via the Hsp90/CKS1 pathway in colon cancer

“…Earlier reports showed that inhibiting Hsp90 can relieve CKS1-induced drug resistance and progression in cancer therapy [13, 14]. Increasing evidences have shown that inhibitors of Hsp90, such as AUY922, 17-AAG, TAS-116, and NCT-50, have significant antitumor activity [15–19]. According to the previously study, we speculate that Hsp90 and CKS1 may crosstalk with each other to take part in tumorigenesis, which still need further study.…”

Complex Crystal Structure Determination and in vitro Anti–non–small Cell Lung Cancer Activity of Hsp90N Inhibitor SNX-2112

“…However, drug resistance and toxicity confined their clinical applications ( Tomasini et al, 2016 ; Xiong et al, 2019 ). Hsp90, as a chaperone, plays a vital and even decisive role in tumorigenesis and development by assisting 300 client proteins to obtain their correct folding and mature conformation ( Jhaveri et al, 2014 ; Hyun et al, 2018 ). Hsp90 exists with an α-α or β-β homodimer in the cytoplasm, and each monomer consists of three domains.…”

“…Among the client proteins, 48 proteins play an important, even decisive role in tumorigenesis and development, such as transmembrane tyrosine kinase, steroid receptors, and cell cycle regulators, etc. ( Jhaveri et al, 2014 ; Hyun et al, 2018 ). Hsp90 N inhibitors lead to multiple misfolded or immature client proteins to be degraded by the ubiquitin protease complex pathway ( Chen et al, 2014 ), which involves simultaneous intervention of multiple potential antitumor target proteins and a “multipoint attack” on the tumor to achieve favorable therapeutic efficacy ( Chehab et al, 2015 ; Dutta Gupta et al, 2019 ).…”

Impact of HDAC Inhibitors on Protein Quality Control Systems: Consequences for Precision Medicine in Malignant Disease

“…Thus, it reduces the likelihood of the tumor acquiring resistance to any single therapeutic pathway and is a major advantage upon other agents (Banerji, 2009). However, HSP90 inhibitors such as 17-AAG have not reached clinical trials beyond phase III, due to minimal effects and toxicity, especially liver toxicity (Hyun et al, 2018). Therefore, the combination with other agents, for instance HDACi, could be a promising alternative, in order to reduce the effective concentration of HSP90 inhibitors.…”