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Rational design, synthesis, and biological evaluation of novel C6-modified geldanamycin derivatives as potent hsp90 inhibitors and anti-tumor agents

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Chinese Chemical Letters 2023年第2期34卷 434-439页

作者： Ruxuan Wang Rentao Zhang Haoran Yang Nina Xue Xiaoguang Chen Xiaoming Yu State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Heat shock protein 90(hsp90) is an appealing anticancer drug target that provoked a tremendous wave of investigations. Geldanamycin(GA) is the first identified hsp90 inhibitor that exhibited potent anticancer activity, but the off-target toxicity associated with the benzoquinone moiety hampered its clinical application. Until now, structure optimization of GA is still in need to fully exploit the therapeutic value of hsp90. Due to the structural complexity and synthetic challenge of this compound family, conventional optimization is bound to be costly but high efficiency is expected to be reachable by combining the art of rational design and total synthesis. Described in this paper is our first attempt at this approach aiming at rational modification of the C6-position of GA. The binding affinities towards hsp90 of compound 1(C6-ethyl) and 2(C6-methyl) were designed and predicted by using Discovery Studio. These compounds were synthesized and further subjected to a thorough in vitro biological evaluation. We found that compounds1 and 2 bind to hsp90 protein with the IC_(50) of 34.26 nmol/L and 163.7 nmol/L, respectively. Both compounds showed broad-spectrum antitumor effects. Replacing by ethyl, compound 1 exhibited more potent bioactivity than positive control GA, such as in G2/M cell cycle arrest, cell apoptosis and client proteins degradations. The results firstly indicated that the docking study is able to provide a precise prediction of hsp90 affinities of GA analogues, and the C6 substituent of GA is not erasable without affecting its biological activity.

关键词： hsp90 inhibitors Geldanamycin derivatives Total synthesis Structure-activity relationship Anticancer

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PGK1-coupled hsp90 stabilizes GSK3βexpression to regulate the stemness of breast cancer stem cells

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Cancer Biology & Medicine 2022年第4期19卷 486-503页

作者： Wei Tang Yu Wu Xin Qi Rilei Yu Zhimin Lu Ao Chen Xinglong Fan Jing Li Key Laboratory of Marine Drugs Chinese Ministry of EducationSchool of Medicine and PharmacyOcean University of ChinaQingdao 266003China Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease of the First Affiliated Hospital Institute of Translational MedicineZhejiang UniversityHangzhou 310029China Department of Thoracic Surgery Qilu Hospital(Qingdao)Cheeloo College of MedicineShandong UniversityQingdao 266003China Open Studio for Druggability Research of Marine Natural Products Pilot National Laboratory for Marine Science and Technology(Qingdao)Qingdao 266003China Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology Qingdao 266003China

Objective:Glycogen synthase kinase-3β(GSK3β)has been recognized as a suppressor of Wnt/β-catenin signaling,which is critical for the stemness maintenance of breast cancer stem ***,the regulatory mechanisms of GSK3βprotein expression remain ***:Co-immunoprecipitation and mass spectral assays were performed to identify molecules binding to GSK3β,and to characterize the interactions of GSK3β,heat shock protein 90(hsp90),and *** role of PGK1 in hsp90 chaperoning GSK3βwas evaluated by constructing 293T cells stably expressing different domains/mutants of hsp90α,and by performing a series of binding assays with bacterially purified proteins and clinical *** influences of hsp90 inhibitors on breast cancer stem cell stemness were investigated by Western blot and mammosphere formation ***:We showed that GSK3βwas a client protein of ***90,which did not directly bind to GSK3β,interacted with phosphoglycerate kinase 1 via its C-terminal domain,thereby facilitating the binding of GSK3βto ***3β-bound PGK1 interacted with hsp90 in the“closed”conformation and stabilized GSK3βexpression in an hsp90 activity-dependent *** hsp90 inhibitor,17-AAG,rather than HDN-1,disrupted the interaction between hsp90 and PGK1,and reduced GSK3βexpression,resulting in significantly reduced inhibition ofβ-catenin expression,to maintain the stemness of breast cancer stem ***:Our findings identified a novel regulatory mechanism of GSK3βexpression involving metabolic enzyme PGK1-coupled hsp90,and highlighted the potential for more effective cancer treatment by selecting hsp90 inhibitors that do not affect PGK1-regulated GSK3βexpression.

关键词： Glycogen synthase kinase-3β(GSK3β) heat shock protein 90(hsp90) phosphoglycerate kinase 1(PGK1) hsp90 inhibitors breast cancer stem cell

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Fluorescent ligand fishing combination with in-situ imaging to screen hsp 90 inhibitors from natural products based on microkernel-based mesoporous fluorescent nanoparticles

Fluorescent ligand fishing combination with in-situ imaging ...

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中国化学会第22届全国色谱学术报告会及仪器展览会

作者： Yue Hu Dong Zhu Nanjing University of Chinese Medicine

＜正＞Heat shock protein 90（hsp 90）, an evolutionarily conserved molecular chaperone, can guide multiple proteins turnover, degradation and activity. In cancerous cells, oncoproteins are often overexpressed and/or mutated, and compared with other heat-related proteins, higher activity of hsp 90 than normal cells participates in key processes oncogenesis such as maintenance of malignancy.

关键词： Ligand fishing hsp90 inhibitors In-situ imaging Natural products Mass spectrometry

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Discovery and development of natural heat shock protein 90 inhibitors in cancer treatment

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Acta Pharmaceutica Sinica B 2012年第3期2卷 238-245页

作者： Yong Li Dongmei Zhang Jun Xu Junmin Shi Lei Jiang Nan Yao Wencai Ye College of Pharmacy Jinan UniversityGuangzhou 510632China Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research Jinan UniversityGuangzhou 510632China School of Biomedical Science The Chinese University of Hong KongHong KongChina

Heat shock protein 90(hsp90)is a highly conserved molecular chaperone that plays a vital role in the signal transduction of ***90 inhibitors are able to inhibit hsp90 or the complex of hsp90 and co-chaperones resulting in the degradation of hsp90-dependent client proteins through the ubiqui tina tion-proteasome pathway,thereby leading to the growth inhibition of tumor *** review will briefy discuss the molecular structure and biological function of hsp90,and focus on a summary of recent progress in the development and testing of natural hsp90 inhibitors and their different means by which they interact with hsp90.

关键词： Heat shock protein 90(hsp90) Tumor hsp90 inhibitors Geldanamycin

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