Article
Chemistry, Multidisciplinary
Subhabrata Chaudhury, Penchala Narasimharao Meka, Monimoy Banerjee, Caitlin N. Kent, Brian S. J. Blagg
Summary: Hsp90 is responsible for folding and trafficking proteins associated with cancer progression. Existing inhibitors have undesired effects, leading to the development of isoform-selective inhibitors. Research shows that Hsp90 beta-selective inhibitors can overcome the detriments of pan-inhibition of Hsp90.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Article
Chemistry, Multidisciplinary
Ruxuan Wang, Rentao Zhang, Haoran Yang, Nina Xue, Xiaoguang Chen, Xiaoming Yu
Summary: Heat shock protein 90 (Hsp90) is an attractive target for anticancer drugs, and Geldanamycin (GA) is the first identified Hsp90 inhibitor. However, the toxicity associated with the benzoquinone moiety of GA limits its clinical application. This study aimed to modify the C6-position of GA and evaluated the anticancer activity of the modified compounds. The results showed that the modified compounds exhibited stronger antitumor effects.
CHINESE CHEMICAL LETTERS
(2023)
Article
Biochemistry & Molecular Biology
Tingting He, Shulei Zhu, Wei Lu
Summary: Heat shock protein 90 (HSP90) is a promising target for anticancer drugs. In this study, a series of novel HSP90 inhibitors was synthesized and compound 6u exhibited the most potent anti-proliferative activity, particularly in Capan-1 cell line. Molecular modeling studies also confirmed the interaction mechanism between 6u and HSP90, suggesting it as a potential candidate for further research.
MOLECULAR DIVERSITY
(2023)
Article
Chemistry, Medicinal
Meng Li, Xianlan She, Yufei Ou, Jiangxin Liu, Zaifeng Yuan, Qin-shi Zhao
Summary: Hsp90 is an ATP-dependent chaperone that plays a crucial role in protein assembly and folding. It has been found to be involved in cancer, viral infection, neurodegenerative disease, and inflammation. In this study, a series of novel analogues were designed, synthesized, and evaluated for their inhibitory activity against Hsp90. Among these analogues, compound 29 and 31 showed the most potent inhibitory activity. Mechanism studies revealed that compound 29 promoted cell apoptosis through the mitochondrial-mediated pathway. Furthermore, compound 29 exhibited anti-tumor activity in a mouse model and showed low acute toxicity. These findings suggest that compound 29 has potential for further development as a therapeutic agent.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Min Xin, Haoyu Wu, Yuan Du, Sheng Liu, Feng Zhao, Xiaofeng Mou
Summary: In order to replace non-steroidal anti-inflammatory drugs (NSAIDs) with the risk of heart attack and stroke, there is an urgent need to develop a new type of highly efficient and low-toxic selective COX-2 inhibitor. We synthesized 38 resveratrol amide derivatives and evaluated their COX-1/COX-2 inhibitory activities. Compounds 8a, 6a, 8c, and 13c showed important inhibitory activity against COX-2 with definite selectivity. Compound 8a exhibited evident anti-inflammatory effect without gastric ulcer toxicity and is worthy of further study.
CHEMICO-BIOLOGICAL INTERACTIONS
(2023)
Article
Biochemistry & Molecular Biology
Xiaoyi Zhang, Tong Zhao, Minghao Sun, Pei Li, Mengzhen Lai, Lingfeng Xie, Jiaying Chen, Jian Ding, Hua Xie, Jinpei Zhou, Huibin Zhang
Summary: Several small-molecule covalent inhibitors of KRASG12C have shown promising breakthroughs in treating KRAS mutant cancer. However, adaptive resistance may limit the clinical application of these inhibitors. The emerging PROTAC strategy offers complementary advantages and improves anti-tumor efficacy. Through protein degradation and anti-proliferative activities, novel KRASG12C-PROTACs have been demonstrated to effectively bind and degrade KRASG12C, surpassing the potency of AMG-510. Mechanistic studies indicate degradation effects through the ubiquitin-proteasome pathway. These findings support the use of PROTACs for degrading the oncogene KRASG12C and provide insights for optimizing the structure of KRASG12C-PROTACs.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Yiqing Yang, Tongke Tang, Xiaolu Li, Thomas Michel, Liqin Ling, Zhenghui Huang, Maruthi Mulaka, Yue Wu, Hongying Gao, Liguo Wang, Jing Zhou, Brigitte Meunier, Hangjun Ke, Lubin Jiang, Yu Rao
Summary: This study identified a novel multi-targeting antimalarial molecule RYL-581 through structure-based drug design, which binds to multiple protein binding sites of Plasmodium falciparum. The compound effectively kills various drug-resistant strains in vitro and exhibits good solubility as well as in vivo activity, suggesting its potential in future drug discovery projects targeting membrane-associated targets.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Chemistry, Medicinal
Bin Zhang, Zhikun Liu, Shengjin Xia, Qingqing Liu, Shaohua Gou
Summary: Multi-target, especially dual-target, drug design is a popular research field in cancer treatment. This study developed quinazoline derivatives as dual EGFR/CAIX inhibitors, with compound 8v showing potent anticancer activity against mutant-type lung cancer cells, especially under hypoxic conditions. Mechanism studies revealed that 8v exhibited strong inhibitory effects on both EGFR(T790M) and CAIX enzymes, making it a promising candidate for further research in cancer therapy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Organic
Changpeng Chen, Zhijun Wang, Sha Wang, Liang Xu, Xiaoming Zeng
Summary: We describe the selective cyclization of anilines with cyclobutanones and congeners using chromium catalysis. This reaction enables the formation of diastereoselective tetrahydroquinolines by linking two strained four-membered rings, leading to the synthesis of cyclobutane-fused and constrained spirotetrahydroquinolines (STHQs) and complex multiple spiro carbon-containing polyazacycles. The constrained STHQs have been utilized as versatile precursors for the synthesis of oxygen-, nitrogen-, and thio-substituted spiro analogues, as well as dioxygen-incorporated spiroazacycles.
Article
Chemistry, Medicinal
Gabriel Jasinski, Emir Salas-Sarduy, Daniel Vega, Lucas Fabian, M. Florencia Martini, Albertina G. Moglioni
Summary: Based on literature data, a QSAR model was developed to predict the activity of TSCs. New TSCs were designed and tested against CZP, resulting in highly potent inhibitors. Molecular docking and QM/QM ONIOM refinement studies confirmed the expected binding mode for the active TSCs. Kinetic experiments showed that the new TSCs act through the formation of a reversible covalent adduct. These findings highlight the effectiveness of QSAR and molecular modeling techniques in the design of potent CZ/CZP inhibitors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Xinran Wang, Cai Zhang, Xiangyu Zhang, Jiming Wang, Liyu Zhao, Dongmei Zhao, Maosheng Cheng
Summary: In this study, a series of 2-aminopyrimidine derivatives were designed and synthesized as LSD1 inhibitors based on the AZD9291 skeleton. The most promising compound, X43, showed remarkable LSD1 selectivity and inhibitory activity against cell proliferation. It also induced apoptosis in A549 cells.
BIOORGANIC CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Qi-Hang Cui, Wen-Bo Li, Zhao-Yang Wang, Kai-Yan Xu, Shuai Wang, Jian-Tao Shi, Li-Wen Zhang, Shi-Wu Chen
Summary: The structure of BRD(4)i ABBV-075 was modified and a novel series of coumarin derivatives were synthesized as BRD4 inhibitors. Compound 27d showed excellent inhibitory activities against various cancer cells and exhibited good stability, indicating it as a promising lead compound for further drug development.
BIOORGANIC CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Elena Bechthold, Julian A. Schreiber, Nadine Ritter, Dirk Schepmann, Constantin Daniliuc, Guiscard Seebohm, Bernhard Wuensch
Summary: N-Methyl-D-aspartate (NMDA) receptors with GluN2B subunits are important in neurodegenerative diseases. By modifying eliprodil, compounds with high affinity for GluN2B receptors were created. However, these compounds also have high affinity for sigma1 and sigma2 receptors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Dong Liang, Chen Yu, Zhao Ma, Mingzhao Hu, Jiahui Wang, Xuhui Dong, Lupei Du, Minyong Li
Summary: In this study, the discovery of two series of parbendazole derivatives as tubulin inhibitors for the treatment of head and neck squamous cell carcinoma (HNSCC) was reported. Compound 9q exhibited the best pharmacological activities and pharmacokinetic properties, displaying reasonable inhibition activity on cell proliferation, induction of cell apoptosis, and suppression of cell migration and invasion.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Guang-Jing Feng, Yang-Fan Guo, Yuming Tang, Min Li, Yufei Jia, Zhimeng Li, Shuangshuang Wang, Hongmei Liu, Yuzhou Wu, Hai Dong
Summary: The potential of thioglucoside analogues as antidiabetic drugs was investigated in this study. The analogues showed good stability, low toxicity, and high inhibitory activity, making them promising candidates for new gliflozin drugs. Additionally, the synthesis of these analogues is simple, efficient, and cost-effective.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Christopher M. Brackett, Brian S. J. Blagg
Summary: SUMOylation is an important post-translational modification involving the attachment of SUMO polypeptide to target proteins. Dysregulation of SUMOylation pathway is observed in cancer and neurological diseases, with upregulated SUMO enzymes correlated with prognosis and disease progression. Inhibitors of SUMOylation are being actively researched, including natural products, peptidomimetics, and synthetic derivatives identified via virtual screens.
CURRENT MEDICINAL CHEMISTRY
(2021)
Article
Surgery
Chitra Subramanian, Rebecca Gorney, Ton Wang, Derek Ge, Nina Zhang, Ang Zuo, Brian S. J. Blagg, Mark S. Cohen
Summary: The study reveals that lenvatinib-resistant thyroid cancer cells exhibit increased dependency on glycolysis, which can be effectively treated by targeting key glycolytic genes, proteins, and long non-coding ribonucleic acids with KU757.
Review
Chemistry, Medicinal
Subhabrata Chaudhury, Bradley M. Keegan, Brian S. J. Blagg
Summary: Heat shock proteins (Hsps) act as molecular chaperones and are involved in the activation of the heat shock response (HSR) to counter abnormal physiological conditions and stress, potentially helping in conditions such as cancer and neurodegenerative diseases. Cellular stress results in the upregulation of Hsp70 transcription to protect cells, with Hsp90 being the primary regulator of the HSR and a potential target for therapeutic interventions in neuropathies.
MEDICINAL RESEARCH REVIEWS
(2021)
Article
Chemistry, Medicinal
Sanket J. Mishra, Weiya Liu, Kristin Beebe, Monimoy Banerjee, Caitlin N. Kent, Vitumbiko Munthali, John Koren, John A. Taylor, Leonard M. Neckers, Jeffrey Holzbeierlein, Brian S. J. Blagg
Summary: Hsp90 proteins play a crucial role in cancer progression, and inhibiting their activity may be beneficial for cancer treatment. Current Hsp90 inhibitors target all isoforms, potentially leading to adverse effects. Utilizing Hsp90 beta-selective inhibitors as a new approach for cancer therapy holds promise in reducing side effects.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Sanket J. Mishra, Anuj Khandelwal, Monimoy Banerjee, Maurie Balch, Shuxia Peng, Rachel E. Davis, Taylor Merfeld, Vitumbiko Munthali, Junpeng Deng, Robert L. Matts, Brian S. J. Blagg
Summary: The study focuses on a new class of anti-cancer agents targeting Hsp90 protein - Hsp90 alpha-selective inhibitors, which demonstrate specificity and broad selectivity, showing promise for significant impact in cancer treatment.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Review
Cell Biology
Patricija van Oosten-Hawle, Steven Bergink, Brian Blagg, Jeff Brodsky, Adrienne Edkins, Brian Freeman, Olivier Genest, Linda Hendershot, Harm Kampinga, Jill Johnson, Antonio De Maio, Dan Masison, Kevin Morano, Gabriele Multhoff, Chris Prodromou, Veena Prahlad, Ruth Scherz-Shouval, Anastasia Zhuravleva, Mehdi Mollapour, Andrew W. Truman
Summary: The CSSI organized a virtual meeting on November 5-6, 2020, aiming to provide an international platform for scientists in the field of cell stress and chaperones to exchange data and ideas during the Covid-19 pandemic.
CELL STRESS & CHAPERONES
(2021)
Article
Immunology
A. L. Heck, S. Mishra, T. Prenzel, L. Feulner, E. Achhammer, V Saerchen, B. S. J. Blagg, W. Schneider-Brachert, S. Schuetze, J. Fritsch
Summary: The study reveals that extrinsic cell death activation via TNF or TRAIL results in HSP90 beta degradation, promoting apoptosis induction.
Article
Chemistry, Medicinal
Dilip K. Tosh, Christopher M. Brackett, Young-Hwan Jung, Zhan-Guo Gao, Monimoy Banerjee, Brian S. J. Blagg, Kenneth A. Jacobson
Summary: The Grp94 isoform-selective inhibitor NECA has been identified as a promising molecule for the treatment of cancer and neurodegenerative diseases. Further studies are needed to develop inhibitors with the NECA scaffold that maintains selectivity towards Grp94.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Review
Pharmacology & Pharmacy
Monimoy Banerjee, Ishita Hatial, Bradley M. Keegan, Brian S. J. Blagg
Summary: Hsp90 is a molecular chaperone essential for the maturation of diverse client proteins, some of which are cancer targets. Inhibiting Hsp90 activity offers potential for drug development in treating diseases such as cancer. Various assays and technologies are being used to find specific and potent Hsp90-targeting drugs.
PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Chemistry, Organic
Vishal C. Birar, Gene Zaid, Brian S. J. Blagg
Summary: The combination of herbal medicine and nutraceutical components can produce compounds with reduced toxicity for the treatment of human diseases such as cancer. Research has shown that specific combinations can exhibit activity against various human cancer cell lines.
TETRAHEDRON LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Yssa A. Rodriguez, Sukmanjit Kaur, Erika Nolte, Zhang Zheng, Brian S. J. Blagg, Rick T. Dobrowsky
Summary: Diabetic peripheral neuropathy (DPN) is linked to altered mitochondrial bioenergetics (mtBE), and KU-596 is a small molecule neurotherapeutic that can reverse DPN symptoms by improving sensory neuron mtBE and decreasing pro-oxidant protein Txnip. This study found that KU-596 therapy improved DPN, mtBE, and mitophagy in a manner dependent on Hsp70 but not Txnip. The results suggest that KU-596 may enhance mitochondrial tolerance to diabetic stress through a mechanism involving Hsp70 and Txnip.
ACS CHEMICAL NEUROSCIENCE
(2021)
Review
Pharmacology & Pharmacy
Michael A. Serwetnyk, Brian S. J. Blagg
Summary: Hsp90 is a crucial molecular chaperone with potential as a target for cancer therapy. In addition to known inhibitory mechanisms, alternative approaches for Hsp90 inhibition are being explored.
ACTA PHARMACEUTICA SINICA B
(2021)
Meeting Abstract
Biochemistry & Molecular Biology
Kerry Chou, Christopher Brackett, Sanket Mishra, Brian Blagg, John Streicher
Meeting Abstract
Oncology
C. Subramanian, J. Zhu, D. Lubman, B. S. Blagg, M. S. Cohen
ANNALS OF SURGICAL ONCOLOGY
(2021)
Meeting Abstract
Oncology
M. K. Chanda, C. Subramanian, J. Sanchez, B. S. Blagg, M. S. Cohen, K. Spielbauer
ANNALS OF SURGICAL ONCOLOGY
(2021)
