Journal ArticleDOI
Inhibition of HSP90 molecular chaperones: moving into the clinic.
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TLDR
The current status of HSP90 inhibitors in clinical development is reviewed, including geldanamycin derivatives, resorcinol derivatives, purine analogues, and other synthetic inhibitors.Abstract:
Summary Heat shock protein 90 (HSP90) is a molecular chaperone that is crucial for the stability and function of many proteins essential for cell survival. Many oncogenes, including tyrosine kinases, transcription factors, and cell-cycle regulatory proteins, are client proteins of HSP90. Inhibition of HSP90 causes client protein degradation via the ubiquitin–proteasome pathway, and is a mechanism that might simultaneously downregulate several redundant pathways crucial for cell viability and tumour development. HSP90 inhibitors are currently being developed as anticancer agents, and have shown early promising results in molecularly defined subgroups of solid tumours (eg, ALK-rearranged non-small-cell lung cancer and HER2-amplified breast cancer) and some haematological malignancies (eg, multiple myeloma). Here, we review the current status of HSP90 inhibitors in clinical development, including geldanamycin derivatives, resorcinol derivatives, purine analogues, and other synthetic inhibitors. We also discuss novel strategies and future perspectives on how to optimise the therapeutic potential of this exciting new class of drugs.read more
Citations
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Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications
Jacek Zielonka,Joy Joseph,Adam Sikora,Micael Hardy,Olivier Ouari,Jeannette Vasquez-Vivar,Gang Cheng,Marcos Lopez,Balaraman Kalyanaraman +8 more
TL;DR: The physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes, and sensors, and examples of mitochondrial targeting of bioactive compounds are described.
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The Biology of Aging and Cancer: A Brief Overview of Shared and Divergent Molecular Hallmarks
TL;DR: It is now clear that aging and cancer development either share or diverge in several disease mechanisms, and aging can be considered an aging disease, though the shared mechanisms underpinning the two processes remain unclear.
Journal ArticleDOI
LncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc.
Jiayin Tang,Tingting Yan,Yujie Bao,Chaoqin Shen,Chenyang Yu,Xiaoqiang Zhu,Xianglong Tian,Fangfang Guo,Qian Liang,Qiang Liu,Ming Zhong,Jinxian Chen,Zhi-Zheng Ge,Xiao-Bo Li,Xiaoyu Chen,Yun Cui,Ying-Xuan Chen,Weiping Zou,Haoyan Chen,Jie Hong,Jing-Yuan Fang +20 more
TL;DR: The lncGLCC1 is significantly upregulated under glucose starvation in CRC cells, supporting cell survival and proliferation by enhancing glycolysis and correlates with poor prognosis in this cancer.
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Molecular characterization and targeted therapeutic approaches in breast cancer
TL;DR: The current state of novel biological markers for BC, the evidence to demonstrate their clinical validity and utility, and the implication for therapeutic targeting are reviewed.
Journal ArticleDOI
Tumor-educated B cells selectively promote breast cancer lymph node metastasis by HSPA4-targeting IgG.
Yan Gu,Yanfang Liu,Li Fu,Lili Zhai,Jie Zhu,Yanmei Han,Yingming Jiang,Yi Zhang,Peng Zhang,Zhengping Jiang,Xiang Zhang,Xuetao Cao,Xuetao Cao,Xuetao Cao +13 more
TL;DR: A mouse model of spontaneous lymph node metastasis of breast cancer shows that primary tumors induced B cell accumulation in draining lymph nodes, identifying a key role for tumor-educated B cells and their derived antibodies in lymph node premetastatic niche formation, providing potential targets for cancer intervention.
References
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Journal ArticleDOI
MPC-3100, a fully synthetic, orally bioavailable Hsp90 inhibitor, in cancer patients.
Margaret K. Yu,W. E. Samlowski,Vijay Baichwal,Brita Brown,B. A. Evans,D. Woodland,G. Mather,Amita Patnaik,Anthony W. Tolcher,Kyri Papadopoulos +9 more
TL;DR: This study is designed to determine the safety and tolerability of daily oral administration of MPC-3100, a fully synthetic, orally bioavailable, Hsp90 inhibitor, and characterizing pharmacokinetics and assessing anti-tumor activity.
Journal ArticleDOI
Action of SDF-1/CXCR4 axis in liver metastasis of colorectal cancer.
Shinichiro Yamada,Mitsuo Shimada,Toru Utsunomiya,Satoru Imura,Yuji Morine,Tetsuya Ikemoto,Hiroki Mori,Jun Hanaoka,Yu Saito,Michihito Asanoma,Hidenori Miyake +10 more
TL;DR: It is suggested that an enhanced expression of SDF-1 in non-tumor liver tissues may have an important role in the formation of liver metastasis and poor prognosis of the patients with colorectal Liver metastasis.
Journal ArticleDOI
Phase l study assessing a two-consecutive-day (QD x 2) dosing schedule of the HSP90 inhibitor, AT13387, in patients with advanced solid tumors.
Khanh Tu Do,Giovanna Speranza,Alice P. Chen,Jane B. Trepel,Min-Jung Lee,Sunmin Lee,Larry Phillips,Jerry M. Collins,Marcie K. Weil,Robert J. Kinders,Sonny Khin,Deborah Allen,Ramya Parthasarathy,James H. Doroshow,Shivaani Kummar +14 more
TL;DR: To determine toxicity, MTD, PK, and pharmacodynamic (PD) effect of AT13387 given IV QD x 2, 3 weeks out of 4 patients with advanced cancers progressing following standard therapy is determined.
Journal ArticleDOI
A phase I dose-escalation study of the HSP90 inhibitor AUY922 and erlotinib for patients with EGFR-mutant lung cancer with acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs).
Melissa Lynne Johnson,Helena Alexandra Yu,Eric M. Hart,Rebekah Worden,Alfred Rademaker,Rajesh Gupta,Claire Miller,Jyoti D. Patel,Mark G. Kris,Vincent A. Miller,Gregory J. Riely +10 more
TL;DR: AUY922 is a highly potent, non-geldanamycin analog, HSP90 inhibitor that degrades mutated EGFR and MET and has anti-tumor activi... as discussed by the authors.
Journal ArticleDOI
Biomarkers that predict sensitivity to heat shock protein 90 inhibitors (HSP90i).
Komal Jhaveri,Neil M. Iyengar,Adriana D. Corben,Sujata Patil,Muzaffar Akram,Russell Towers,Rita A. Sakr,Clifford A. Hudis,Tari A. King,Neal Rosen,Sarat Chandarlapaty,Shanu Modi +11 more
TL;DR: Predictive biomarkers could identify patients (pts) and/or tumors with sensitivity to HSP90i improving the therapeutic index and explore potential biomarkers across multiple studies of H SP90i.