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Heat Shock Protein 90 (Hsp90) Inhibitory Potentials of Some Chalcone Compounds as Novel Anti-Proliferative Candidates
Published in P. Mereena Luke, K. R. Dhanya, Didier Rouxel, Nandakumar Kalarikkal, Sabu Thomas, Advanced Studies in Experimental and Clinical Medicine, 2021
Debarshi Kar Mahapatra, Sayan Dutta Gupta, Sanjay Kumar Bharti, Tomy Muringayil Joseph, Józef T. Haponiuk, Sabu Thomas
Therefore, Hsp90 inhibitor never suppresses the cellular proteins and is therefore considered as less-toxic [32]. The above facts provided the impetus for the design and discovery of novel Hsp90 inhibitors for the treatment of cancer.
Novel Anti-Cancer Drugs Based On Hsp90 Inhibitory Mechanisms: A Recent Report
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
It has been 23 years since Hsp90 was proved as a druggable candidate. Since then, researchers have failed in getting a single Hsp90 inhibitors approved by regulatory authorities. This failure warrants urgent introspection of the strategy involved in the whole discovery process. Several scientists have tried to pass the buck on Hsp90 as a target selection. One major reason for this assumption is similar topology of the nucleotide-binding site of Hsp90 and normal ATP binding enzymes and proteins. However, it was experimentally proved that the morphology of Hsp90’s ATP binding cleft is different from that of the healthy cellular enzyme’s/protein’s ATP binding site. In Hsp90, this cleft assumes a ‘V’ shaped configuration, whereas in normal protein, this site adopts a straight morphology [54–56]. Hence, blaming Hsp90 alone will be a gross injustice to this wonderful target. It can be regarded as a culprit for development and progression of cancer but cannot be a convict in anticancer drug discovery. Therefore, we tried to analyze the drug designing strategy adopted for identifying novel Hsp90 inhibitors. The two rational drug-designing approaches involved in the discovery of antagonist against Hsp90 are structure-based approach (virtual screening, molecular docking) [131–133] and ligand-dependent methodology (QSAR techniques) [128, 132–136]. The challenges with the two designing approaches are discussed in the underlying sections.
Discovery of potent heat shock protein 90 (Hsp90) inhibitors: structure-based virtual screening, molecular dynamics simulation, and biological evaluation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Yonghua Xu, Yunting Zou, Shasha Zhou, Miao-Miao Niu, Yan Zhang, Jindong Li, Zhen Xu, Li Yang
In this study, the X-ray crystallographic structure of Hsp90 protein (PDB ID: 2XJX) complex with the original ligand was retrieved from the protein data bank. After the Hsp90 protein was prepared by removing water, adding polar hydrogen bonds, merging non-polar hydrogen bonds, and calculating gasteiger charges using MOE, this protein was used to establish a Hsp90 pharmacophore model. Based on the interaction analysis of Hsp90 and the original ligand, a pharmacophore model consisting of one hydrogen-bond donor (F1), one aromatic centre (F2), and two hydrophobic features (F3 and F4) was generated (Figure 2). The F1 feature overlapped the hydroxyl group of the original ligand, which formed the hydrogen-bond interaction with the carboxylate of Asp93. The hydrophobic feature F3 formed a hydrophobic interaction with Ala55. The F2 and F4 which mapped the aromatic ring and hydrophobic group of the ligand, respectively, formed hydrophobic interactions with the side chain benzene ring of Phe138. The pharmacophore features described above were used for subsequent virtual screening of Hsp90 inhibitors.
Design, synthesis, biological evaluation and molecular docking study of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as novel HSP90 N-terminal inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Man Yang, Chenyao Li, Yajing Li, Chen Cheng, Meiyun Shi, Lei Yin, Hongyu Xue, Yajun Liu
HSP90 consists of three domains: the N-terminus, C-terminus, and the middle domain15,16. Classical HSP90 inhibitors competitively bind to the ATP binding pocket at the N-terminus. Over twenty HSP90 N-terminal inhibitors have entered clinical trials for the treatment of a variety of cancers17,18. Allosteric binding sites are also found at the C-terminus and the middle domain. HSP90 C-terminal inhibitors have been extensively studied in recent years because they do not cause a rescue cascade known as the heat shock response, which is often observed in the modulation of HSP90 with N-terminal inhibitors19,20. Many natural products and synthetic small molecules have been identified as HSP90 C-terminal inhibitors; however, they have not yet entered clinical trials for cancer therapy21.
An updated patent review of anticancer Hsp90 inhibitors (2013-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Li Li, Nan-Nan Chen, Qi-Dong You, Xiao-Li Xu
In summary, we retrospect the functions of Hsp90 in the development of cancer and its inhibitors, including small molecules, peptides, and antibodies published in the patents range from 2013 to present. Many novel chemical skeletons with fewer side effects and superior anticancer potency were identified that significantly extend the structural diversity of Hsp90 inhibitors. Furthermore, with the understanding of Hsp90 isoforms, cell location, and interactions with co-chaperones, inhibitors with different action models have been studied, such as isoform-selective inhibitors and peptides targeting cell surface Hsp90. These novel inhibitors with different mechanisms broaden the Hsp90 inhibitory strategies leading to the increased specificities of Hsp90 inhibitors. It is hoped that through the application of these new strategies, more compounds will enter clinical research in the future and finally enter the market for the benefit of mankind.