• Biomolecules & Therapeutics
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• 제27권5호
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• pp.423-434
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• 2019

HSP90 is a molecular chaperone that increases the stability of client proteins. Cancer cells show higher HSP90 expression than normal cells because many client proteins play an important role in the growth and survival of cancer cells. HSP90 inhibitors mainly bind to the ATP binding site of HSP90 and inhibit HSP90 activity, and these inhibitors can be distinguished as ansamycin and non-ansamycin depending on the structure. In addition, the histone deacetylase inhibitors inhibit the activity of HSP90 through acetylation of HSP90. These HSP90 inhibitors have undergone or are undergoing clinical trials for the treatment of cancer. On the other hand, recent studies have reported that various reagents induce cleavage of HSP90, resulting in reduced HSP90 client proteins and growth suppression in cancer cells. Cleavage of HSP90 can be divided into enzymatic cleavage and non-enzymatic cleavage. Therefore, reagents inducing cleavage of HSP90 can be classified as another class of HSP90 inhibitors. We discuss that the cleavage of HSP90 can be another mechanism in the cancer treatment by HSP90 inhibition.

• Biomolecules & Therapeutics
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• 제24권5호
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• pp.453-468
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• 2016

There is a conserved ATPase domain in topoisomerase II (topo II) and heat shock protein 90 (Hsp90) which belong to the GHKL (gyrase, Hsp90, histidine kinase, and MutL) family. The inhibitors that target each of topo II and Hsp90 are intensively studied as anti-cancer drugs since they play very important roles in cell proliferation and survival. Therefore the development of dual targeting anti-cancer drugs for topo II and Hsp90 is suggested to be a promising area. The topo II and Hsp90 inhibitors, known to bind to their ATP binding site, were searched. All the inhibitors investigated were docked to both topo II and Hsp90. Four candidate compounds as possible dual inhibitors were selected by analyzing the molecular docking study. The pharmacophore model of dual inhibitors for topo II and Hsp90 were generated and the design of novel dual inhibitor was proposed.

• 생명과학회지
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• 제28권10호
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• pp.1212-1219
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• 2018

열 충격 단백질인 heat shock protein 90 (Hsp90)은 종양 형성 과정에서 중요한 역할을 하고 있으며, 이에 따라 1세대 및 2세대 Hsp90저해제들이 개발되어, 다양한 암에서의 항암 효과가 보고되어 있다. 2세대 Hsp90저해제로 개발된 BIIB021는 1세대 Hsp90저해제인 17-allylamino-17-demethoxygeldanamycin (17-AAG)에 내성을 나타내는 항암제 다제내성(MDR) 암세포에 감수성을 가진다고 알려져 있지만, 본 연구에서 BIIB021에 내성인 MDR세포로서, MCF7-MDR 및 HeyA8-MDR세포가 해당됨을 밝혔다. BIIB021 감수성을 증강시키는 물질로 비스테로이드성 항염증약물(NSAID)인 dimethyl-celecoxib (DMC)의 BIIB021의 효과 증강 활성을 BIIB021-내성 및 -감수성 MDR 세포에서 확인하였다. MDR세포에 NSAID와 BIIB021의 병합 처리한 경우, NSAID의 자가분해(autophagy) 유도 활성에 의해 MDR세포에서 과잉 발현하는 변이형 mutant p53 (mutp53)을 분해할 뿐만 아니라 BIIB021 처리로 유도되는 Hsp70 발현을 억제하므로써, 암세포의 BIIB021 내성을 극복할 수 있는 활성을 나타내었다. 또한 NSAID 물질인 sulindac sulfate 및 FDA 승인 약물인 niclosamide 도 자가분해 유도 활성으로 Hsp90의 타켓 단백질 인 mutp53 및 c-Myc의 분해를 유도하므로서, 17-AAG 효과를 증강시켰다. 그러므로 본 연구에서는 새로운 BIIB021에 대한 효과 증강 및 내성 극복 물질로서, NSAIDs 및 niclosamide를 발굴하였으며, 이들 물질의 자가분해 경로 활성화에 의하여, BIIB021 효과를 극대화 시킴을 밝혔다.

• 생명과학회지
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• 제26권7호
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• pp.826-834
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• 2016

본 연구는 Hsp90 inhibitor 및 SIRT1 inhibitor의 병용처리가 항암제 다제내성(MDR) 인간 암세포의 증식 억제에 효과적임을 밝혔다. SIRT1 활성 억제가 Hsp90 inhibitor인 17-AAG의 세포 독성의 효과를 증강시켰으며, 이로 인해 Hsp90 inhibitors에 대한 내성을 극복시킬 수 있음을 인간 자궁암세포인 HeyA8의 MDR 변이주인 HeyA8- MDR 세포에서 확인하였다. SIRT1 inhibitor는 Hsp90 inhibitor에 의한 Hsp90 샤페론 기능 억제를 증강시키며, ubiquitin ligase CHIP의 발현 증강을 유발하여, Hsp90 client protein 인 mutant p53 (mut p53)의 분해를 촉진시킨다. Mut p53 의 발현 감소는 암세포의 Hsp90 inhibitor 내성 획득의 가장 중요한 원인으로 지적되는 heat shock factor 1 (HSF1)/heat shock proteins (Hsps)의 발현 억제와 관련됨을 알 수 있었으며, 이는 항암제 다제내성 세포에서 SIRT1 inhibitor에 의하여 Hsp90 inhibitor에 대한 감수성이 증강되는 분자적 기전임을 밝혔다. 그러므로, SIRT1 억제에 의한 mut p53/HSF1 발현 감소가 MDR 암세포의 Hsp90 inhibitors 내성 극복에 매우 유효함을 시사하는 결과를 얻었다.

• BMB Reports
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• 제42권10호
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• pp.623-630
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• 2009

Hsp90, an evolutionarily conserved molecular chaperone, is involved in the folding, stabilization, activation, and assembly of a wide range of 'client' proteins, thus playing a central role in many biological processes. Especially, several oncoproteins act as Hsp90 client proteins and tumor cells require higher Hsp90 activity than normal cells to maintain their malignancy. For this reason, Hsp90 has emerged as a promising target for anti-cancer drug development. It is still largely unknown how Hsp90 can recognize structurally unrelated client proteins. However, recent progress in structural studies on Hsp90 and its interaction with various co-chaperones has broadened our knowledge of how the Hsp90 ATPase activity, which is essential for its chaperone function, is regulated and coupled with the conformational changes of Hsp90 dimer. This review focuses on the roles of various Hsp90 co-chaperones in the regulation of the Hsp90 ATPase cycle, as well as in the selection of client proteins. In addition, the current development of Hsp90 inhibitors based on the structural information will be discussed.

• Biomolecules & Therapeutics
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• 제32권1호
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• pp.115-122
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• 2024

Heat shock protein (HSP) 90 is expressed in most living organisms, and several client proteins of HSP90 are necessary for cancer cell survival and growth. Previously, we found that HSP90 was cleaved by histone deacetylase (HDAC) inhibitors and proteasome inhibitors, and the cleavage of HSP90 contributes to their cytotoxicity in K562 leukemia cells. In this study, we first established mouse xenograft models with K562 cells expressing the wild-type or cleavage-resistant mutant HSP90β and found that the suppression of tumor growth by the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was interrupted by the mutation inhibiting the HSP90 cleavage in vivo. Next, we investigated the possible function of thioredoxin interacting protein (TXNIP) in the HSP90 cleavage induced by SAHA. TXNIP is a negative regulator for thioredoxin, an antioxidant protein. SAHA transcriptionally induced the expression of TXNIP in K562 cells. HSP90 cleavage was induced by SAHA also in the thymocytes of normal mice and suppressed by an anti-oxidant and pan-caspase inhibitor. When the thymocytes from the TXNIP knockout mice and their wild-type littermate control mice were treated with SAHA, the HSP90 cleavage was detected in the thymocytes of the littermate controls but suppressed in those of the TXNIP knockout mice suggesting the requirement of TXNIP for HSP90 cleavage. We additionally found that HSP90 cleavage was induced by actinomycin D, β-mercaptoethanol, and p38 MAPK inhibitor PD169316 suggesting its prevalence. Taken together, we suggest that HSP90 cleavage occurs also in vivo and contributes to the anti-cancer activity of various drugs in a TXNIP-dependent manner.

• Bulletin of the Korean Chemical Society
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• 제32권9호
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• pp.3229-3232
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• 2011

A FRET-based high-throughput screening system was developed for the discovery of competitive smallmolecule Hsp90 inhibitors. The biarsenical fluorescein derivative FlAsH and dabcyl-conjugated Hsp90 inhibitor GM were employed as the FRET donor and quencher, respectively. The spatial proximity perturbation between FlAsH-labeled Hsp90N and GM-dabcyl upon treatment of a small molecule led to changes in the FRET-induced fluorescence, monitored in a high-throughput fashion.

• BMB Reports
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• 제45권1호
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• pp.1-6
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• 2012

Hsp90 is one of the most conserved molecular chaperones ubiquitously expressed in normal cells and over-expressed in cancer cells. A pool of Hsp90 was found in cancer mitochondria and the expression of the mitochondrial Hsp90 homolog, TRAP1, was also elevated in many cancers. The mitochondrial pool of chaperones plays important roles in regulating mitochondrial integrity, protecting against oxidative stress, and inhibiting cell death. Pharmacological inactivation of the chaperones induced mitochondrial dysfunction and concomitant cell death selectively in cancer cells, suggesting they can be target proteins for the development of cancer therapeutics. Several drug candidates targeting TRAP1 and Hsp90 in the mitochondria have been developed and have shown strong cytotoxic activity in many cancers, but not in normal cells in vitro and in vivo. In this review, recent developments in the study of mitochondrial chaperones and the mitochondria-targeted chaperone inhibitors are discussed.

• 대한임상검사과학회지
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• 제50권4호
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• pp.462-469
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• 2018

HSP90은 세포성장, 분화, 생존에 관련된 다양한 단백질들의 안정화 및 활성조절을 담당 한다. HSP90은 구강을 포함하는 두 경부에 발생하는 편평세포암종의 발생과정에서 점진적으로 증가하는 경향을 나타낸다. 따라서 HSP90 의 발현을 억제함으로서 암을 치료하고자하는 연구가 많이 진행되고 있다. 본 연구에서는 인간의 구강 편평세포암종세포에서 증식과 세포주기에 대한 HSP90 억제제의 효과를 조사하기 위해 구강암 세포주를 대상으로 세포의 생존능 측정, 세포주기분석, 전기영동 분석을 시행하였다. HSP90 억제제 처리 후 세포 증식은 억제되었으며 통계적으로 유효한 성장억제 효과를 나타났고, YD-10B세포와 YD-38세포에 Geldanamycin과 17-AAG를 0, 0.1, 0.3, 1, $10{\mu}M$ 농도로 24 hr 처리한 결과 YD-38에 비해 YD-10B세포가 세포 성장이 현저하게 감소하는 것을 확인하였다. 그 후, 유세포 분석기로 확인해 본 결과 G2 arrest가 관찰되었다. 이상의 연구결과에서 구강암 세포주 YD-10B 세포와 YD-38 세포에서 Geldanamycin은 G2 arrest를 유도하고, $p-GSK-3{\beta}$ pathway를 통하여 세포증식을 억제하여 세포생존을 막는다는 것을 확인하였다. 이를 통해 HSP90 저해제를 이용하여 다양한 암세포주에서 치료 효과를 기대 할 수 있다고 사료된다.

• 한국자기공명학회논문지
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• 제18권1호
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• pp.10-14
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• 2014

Hsp90 is a good drug target molecule that is involved in regulating various signaling pathway in normal cell and the role of Hsp90 is highly emphasized especially in cancer cells. Thus, much efforts for discovery and development of Hsp90 inhibitor have been continued and a few Hsp90 inhibitors targeting the N-terminal ATP binding site are being tested in the clinical trials. There are no metabolic signature molecules that can be used to evaluate the effect of Hsp90 inhibition. We previously found a potential C-domain binder named PPC1 that is a synthetic small molecule. Here we report the metabolomics study to find signature metabolites upon treatment of PPC1 compound in lung cancer cell line, A549 and discuss the potentiality of metabolomic approach for evaluation of hit compounds.