Article
Chemistry, Medicinal
Laura Braconi, Silvia Dei, Marialessandra Contino, Chiara Riganti, Gianluca Bartolucci, Dina Manetti, Maria Novella Romanelli, Maria Grazia Perrone, Nicola Antonio Colabufo, Stefano Guglielmo, Elisabetta Teodori
Summary: New 2,5- and 1,5-disubstituted tetrazoles, and 2,5-disubstituted-1,3,4-oxadiazoles were synthesized and studied as MDR reversers, showing potent inhibitory effects on P-gp transport activity and increasing the antiproliferative effect of doxorubicin in MDR cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Gangyang Wang, Lingling Cao, Yafei Jiang, Tao Zhang, Hongsheng Wang, Zhuoying Wang, Jing Xu, Min Mao, Yingqi Hua, Zhengdong Cai, Xiaojun Ma, Shuo Hu, Chenghao Zhou
Summary: This study demonstrates that anlotinib can reverse multidrug resistance in osteosarcoma cells by inhibiting the efflux function of P-glycoprotein 1 (PGP1) and increasing the intracellular accumulation of chemotherapeutic agents. Anlotinib also stimulates the ATPase activity of PGP1. In animal studies, anlotinib combined with doxorubicin shows a significant decrease in tumor growth rate and tumor size.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Sai-Qi Wang, Qiu-Xu Teng, Shuai Wang, Zi-Ning Lei, Hui-Hui Hu, Hui-Fang Lv, Bei-Bei Chen, Jian-Zheng Wang, Xiao-Jing Shi, Wei-Feng Xu, Hong-Min Liu, Xiao-Bing Chen, Zhe-Sheng Chen, Bin Yu
Summary: The compound WS-716 based on triazolo[1,5-a]pyrimidine was reported as a highly potent, specific, and orally active P-gp inhibitor against MDR cancer, showing therapeutic promise. WS-716 and PTX synergistically inhibited growth of resistant cells, induced apoptosis, and increased sensitivity of MDR tumors to PTX.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Chemistry, Medicinal
Weijie Wang, Qi Wan, Mengru Li, Feng Qu, Hongrui Liu, Ying Chen
Summary: In this study, novel seco-DSPs and seco-DMDCK derivatives were synthesized and evaluated for their chemo-sensitize abilities to paclitaxel in A2780/T cell lines. Compound 27f showed remarkable chemo-sensitization with more than 425-fold reversal ratio in A2780/T cells. Preliminary pharmacological mechanism studies indicated that compound 27f effectively increased the accumulation of paclitaxel and Rhodamine 123 by inhibiting P-gp for reversing multidrug-resistance. These findings suggest that compound 27f may be a potential candidate for further development as a chemosensitizer with MDR reversal activity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Lei Zhang, Yidong Li, Chaohua Hu, Yangmin Chen, Zhuo Chen, Zhe-Sheng Chen, Jian-Ye Zhang, Shuo Fang
Summary: This study reveals CDK6-PI3K as a novel target signaling axis to reverse ABCB1-mediated multidrug resistance for the first time in cancers. Deficiency of CDK6 leads to downregulation of ABCB1 expression and reversal of multidrug resistance.
Article
Chemistry, Physical
Damian Krzyzanowski, Marcin Kruszewski, Agnieszka Grzelak
Summary: Silver nanoparticles (AgNPs) have unique properties that have attracted significant attention, showing antibacterial, antifungal, and anticancer properties. However, they can also exhibit cytotoxic effects and modulate the activity and expression of ABC transporters.
Article
Biochemistry & Molecular Biology
Liadys Mora Lagares, Yunierkis Perez-Castillo, Nikola Minovski, Marjana Novic
Summary: P-gp is an important protein involved in drug efflux and multidrug resistance. Molecular dynamics simulations can provide valuable insights into the binding behavior and conformational changes of P-gp in the presence of different compounds.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Silpa Narayanan, Ying-Fang Fan, Nehaben A. Gujarati, Qiu-Xu Teng, Jing-Quan Wang, Chao-Yun Cai, Yuqi Yang, Anirudh J. Chintalapati, Yixiong Lei, Vijaya L. Korlipara, Zhe-Sheng Chen
Summary: VKNG-1 selectively inhibits ABCG2 transporter and reverses resistance to standard anticancer drugs, providing a potential treatment for ABCG2-mediated MDR in colon cancer.
Article
Pharmacology & Pharmacy
Lei Zhang, Biwei Ye, Yunfeng Lin, Yi-Dong Li, Jing-Quan Wang, Zhuo Chen, Feng-Feng Ping, Zhe-Sheng Chen
Summary: In this study, the researchers investigated the effect of the CDK4/6 inhibitor, ribociclib, on multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) in human epidermoid carcinoma cells. They found that ribociclib increased the efficacy of a P-gp substrate drug, colchicine, by down-regulating the expression of P-gp and increasing its ATPase activity. Docking studies suggested that ribociclib interacted with the drug-substrate binding site of P-gp. Additionally, ribociclib inhibited the drug efflux activity of P-gp, leading to increased intracellular accumulation of doxorubicin. These findings suggest that ribociclib may be a potential agent for combined therapy in cancers with P-gp-mediated MDR.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Atsushi Kodan, Ryota Futamata, Yasuhisa Kimura, Noriyuki Kioka, Toru Nakatsu, Hiroaki Kato, Kazumitsu Ueda
Summary: ABCB1, also known as MDR1 or P-glycoprotein, plays a crucial role in exporting various hydrophobic compounds and serving as a protective physiological barrier in several organs. The mechanism involves an aromatic hydrophobic network triggering a conformational change in ABCB1, leading to a twist-and-squeeze motion that exports hydrophobic substrates directly to the extracellular space, distinct from other transporters.
Article
Pharmacology & Pharmacy
Mahdi Ghadi, Seyed Jalal Hosseinimehr, Fereshteh Talebpour Amiri, Alireza Mardanshahi, Zohreh Noaparast
Summary: P-glycoprotein (P-gp) serves as a vital efflux pump in chemotherapy resistance in human colon cancer. The study demonstrates the synergistic anti-tumor activity of itraconazole and paclitaxel, showing enhanced cytotoxicity and tumor growth suppression. Additionally, Tc-99m-MIBI is identified as an effective radiotracer for monitoring response to treatment in MDR tumors.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Review
Chemistry, Medicinal
Hang Zhang, Haiwei Xu, Charles R. Ashby, Yehuda G. Assaraf, Zhe-Sheng Chen, Hong-Min Liu
Summary: This review highlights the recent achievements in drug design and mechanism studies of newly synthetic P-gp inhibitors in the past 5 years, which will help overcome multidrug resistance in cancer chemotherapy.
MEDICINAL RESEARCH REVIEWS
(2021)
Article
Food Science & Technology
Yajing Fang, Fuqiang Liang, Mengmeng Xia, Weiwei Cao, Siyi Pan, Ting Wu, Xiaoyun Xu
Summary: This study found that certain flavonoids can effectively reverse multidrug resistance mediated by P-glycoprotein (P-gp) by inhibiting its activity, with specific structural groups and substitutions playing a crucial role in their inhibitory effects. Additionally, flavonoids can impact P-gp ATPase activity and expression levels, thereby influencing its drug transport activity.
FOOD AND CHEMICAL TOXICOLOGY
(2021)
Review
Pharmacology & Pharmacy
Mohammad Feyzizadeh, Ashkan Barfar, Zeinab Nouri, Muhammad Sarfraz, Parvin Zakeri-Milani, Hadi Valizadeh
Summary: This review discusses various strategies to overcome multidrug resistance (MDR) in cancer therapy, including conventional synthetic and natural inhibitors, as well as novel approaches such as RNA, monoclonal antibodies, nanobiotechnology, and structural modification techniques. The experts emphasize the importance of understanding the structure of ABC transporters to design rational inhibitors and highlight the potential of herbal products in reversing MDR.
EXPERT OPINION ON DRUG DISCOVERY
(2022)
Article
Biochemistry & Molecular Biology
Yasmeen Cheema, Yusra Sajid Kiani, Kenneth J. J. Linton, Ishrat Jabeen
Summary: Researchers developed a pharmacophore model based on the cryo-EM structure of ABCB1 to screen for new inhibitors, resulting in the identification of six potential inhibitors with distinct chemistries and favorable properties. The compounds exhibited low nanomolar range inhibitory concentrations and two of them were able to resensitize ABCB1-expressing cells to taxol. This study demonstrates the utility of cryo-electron microscopy in drug identification and design.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Peng Li, Yunjiao He, Teng Chen, Kit-Ying Choy, Tsun Sing Chow, Iris L. K. Wong, Xinqing Yang, Wenqin Sun, Xiaochun Su, Tak-Hang Chan, Larry M. C. Chow
Summary: Staphylococcal nuclease domain-containing protein 1 (SND1) is overexpressed in breast cancer and binds to metadherin (MTDH) to stabilize SND1, playing a crucial role in breast cancer initiation and progression. Peptide 4-2 disrupts SND1-MTDH interaction and induces SND1 degradation, potentially serving as a therapeutic option for breast cancer.
MOLECULAR CANCER THERAPEUTICS
(2021)
Review
Chemistry, Multidisciplinary
Larry M. C. Chow, Tak Hang Chan
Summary: Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy, often caused by overexpression of ABC transporter proteins such as P-glycoprotein, MRP1, and BCRP on cancer cell membranes. A promising approach to overcome MDR is the use of flavonoid dimers as potent and selective inhibitors of these transporters. Flavonoid dimers have been shown to effectively inhibit the transporters without toxicity to normal cells. Further research is needed to explore the potential of these flavonoid dimers as clinical candidates for MDR reversal.
CANADIAN JOURNAL OF CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Iris L. K. Wong, Xuezhen Zhu, Kin-Fai Chan, Zhen Liu, Chin-Fung Chan, Tsun Sing Chow, Tsz Cheung Chong, Man Chun Law, Jiahua Cui, Larry M. C. Chow, Tak Hang Chan
Summary: The synthesized triazole-containing flavonoids exhibit potent and selective BCRP inhibitory activity in cells overexpressing BCRP, showing promise for combination therapy to overcome multidrug resistance in cancer.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Chantelle Tsoi, Ruixia Deng, Maxwell Kwok, Bin Yan, Carrie Lee, Hung Sing Li, Chloe Ho Yi Ma, Ruibang Luo, Kam Tong Leung, Godfrey Chi-Fung Chan, Larry Ming-cheung Chow, Ellen N. Poon
Summary: Efficient differentiation and maturation of human pluripotent stem cell-derived cardiomyocytes are essential for their application in research and therapy, and this study has shown that the differentiation schedule plays a critical role in determining both differentiation efficiency and cardiomyocyte maturation.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Materials Science, Multidisciplinary
Lin Gu, Yuanzhang Jiang, Larry M. C. Chow, Zhen Liu, Wei Gao, Yanting Han, Cong Wang, Jinlian Hu
Summary: In this study, peptide-polyurethane/urea hybrids with different peptide contents were synthesized based on the secondary structure of spider silk. These materials showed promising mechanical properties and shape memory effect, making them potential candidates for strain sensors.
MATERIALS & DESIGN
(2022)
Article
Biochemistry & Molecular Biology
Tsz Cheung Chong, Iris L. K. Wong, Jiahua Cui, Man Chun Law, Xuezhen Zhu, Xuesen Hu, Jason W. Y. Kan, Clare S. W. Yan, Tak Hang Chan, Larry M. C. Chow
Summary: This study identified Ac15(Az8)(2) as a potent and non-toxic BCRP inhibitor that can reverse BCRP-mediated drug resistance and inhibit tumor growth.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Pharmacology & Pharmacy
Zhenghua Li, Zhen Liu, Jiacai Wu, Bin Li
Summary: This review provides an overview of recent advances in naturally occurring mRNA delivery platforms and their biomedical applications, as well as discusses the future perspectives on the clinical translation of cell-derived vesicles.
Article
Materials Science, Multidisciplinary
Y. Huang, M. Yang, N. Wang, S. Li, Z. Liu, Z. Li, Z. Ji, B. Li
Summary: This study developed dual-component lipid nanoparticles (LNPs) for efficient intracellular delivery of mRNA to macrophages. By screening a panel of quaternary ammonium compounds, a cationic surfactant with two hexadecyl tails was found to effectively deliver mRNA with the assistance of fusogenic lipids. Further optimization of formulation parameters led to the development of LNPs composed of a surfactant-derived ionizable lipid and a fusogenic lipid, which condensed mRNA and displayed excellent biocompatibility. These LNPs protected exogenous mRNA from nucleases and enabled efficient delivery to hard-to-transfect cells.
MATERIALS TODAY ADVANCES
(2022)
Article
Chemistry, Medicinal
Zhen Liu, Iris L. K. Wong, Jingcheng Sang, Fufeng Liu, Clare S. W. Yan, Jason W. Y. Kan, Tak Hang Chan, Larry M. C. Chow
Summary: We previously identified the flavonoid monomer FM04 as a potent P-glycoprotein (P-gp) inhibitor. In this study, we synthesized photoactive FM04 analogues and used LC-MS/MS to identify the FM04-binding sites on P-gp. Mutations were made around the photocrosslinked sites to validate the results. Through mutational studies, molecular docking, and molecular dynamics simulations, we found that FM04 interacts with Q1193 and I1115 in the nucleotide-binding domain 2 (NBD2) of human P-gp. It was proposed that FM04 inhibits P-gp through two novel mechanisms.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Wenqin Sun, Iris L. K. Wong, Helen Ka-Wai Law, Xiaochun Su, Terry C. F. Chan, Gege Sun, Xinqing Yang, Xingkai Wang, Tak Hang Chan, Shengbiao Wan, Larry M. C. Chow
Summary: Tea polyphenol derivative EC31 is a potent and nontoxic P-gp inhibitor that can reverse multidrug resistance and enhance the efficacy of anticancer drugs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Jason W. Y. Kan, Clare S. W. Yan, Iris L. K. Wong, Xiaochun Su, Zhen Liu, Tak Hang Chan, Larry M. C. Chow
Summary: Biotransformation of flavonoid dimer FD18 resulted in an active metabolite FM04, which exhibited improved druggability and was more potent in reversing P-gp-mediated PTX resistance. FM04 sensitized cancer cells to multiple anticancer drugs by inhibiting P-gp transport activity and stimulating P-gp ATPase. In addition, FM04 enhanced the intestinal absorption of PTX and showed significant antitumor activity in mouse models.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Engineering, Biomedical
Zhen Liu, Zhenghua Li, Bin Li
Summary: The nonviral CRISPR/Cas mRNA delivery systems, using lipid nanoparticles to deliver CRISPR/Cas, minimize immunogenicity and carcinogenicity, and enable transient genome editing, thus reducing potential off-target effects.
ADVANCED NANOBIOMED RESEARCH
(2022)
Article
Chemistry, Medicinal
Shuang Mei, Su Jiang, Yuting Wang, Han Jing, Peng Yang, Miao-Miao Niu, Jindong Li, Kai Yuan, Yan Zhang
Summary: This study identifies a dual-targeting peptide, AP-1, that effectively inhibits variants of concern (VOCs) of SARS-CoV-2 without impairing host cell viability. The findings suggest that AP-1 could be a promising broad-spectrum agent for treating emerging VOCs of SARS-CoV-2.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Hyeonjun Lee, Ju Yeon Lee, Hyunsoo Jang, Hye Young Cho, Minhee Kang, Sang Hyun Bae, Suin Kim, Eunji Kim, Jaebong Jang, Jin Young Kim, Young Ho Jeon
Summary: By using liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance experiments, we identified new chemical moieties that bind to the target sites of the protein of interest, allowing for reversible binding and protein degradation. This method has the potential to expand the application of PROTAC technology.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Yingying Li, Xiyou Du, Xinru Kong, Yuelin Fang, Zhijing He, Dongzhu Liu, Hang Wu, Jianbo Ji, Xiaoye Yang, Lei Ye, Guangxi Zhai
Summary: This study proposes a novel nanoplatform based on the autophagy cascade to overcome the obstacles in chemo-immunotherapy. The platform combines chemotherapy and starvation therapy to initiate pro-death autophagy and enhance antigen presentation, while also remodeling the immunosuppressive tumor microenvironment. Furthermore, the study discovers a new therapeutic direction for the respiration inhibitor 3-bromopyruvic acid (3BP) in cancer treatment. Overall, this study offers an opportunity to improve antitumor efficacy and boost immune responses.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Bingsi Wang, Mingxu Ma, Yusen Dai, Pengfei Yu, Liang Ye, Wenyan Wang, Chunjie Sha, Huijie Yang, Yingjie Yang, Yunjing Zhu, Lin Dong, Shujuan Wei, Linlin Wang, Jingwei Tian, Hongbo Wang
Summary: Breast cancer is a common malignant tumor in women, and drug resistance remains a clinical challenge. In this study, a novel compound, G-5b, was developed with potent antagonistic and degradation activities comparable to the current drug fulvestrant. G-5b also showed improved stability and solubility. Mechanistically, G-5b engages the proteasome pathway to degrade ER, inhibiting the ER signaling pathway and inducing apoptosis and cell cycle arrest. In animal models, G-5b exhibited superior pharmacokinetics and pharmacodynamics properties. Overall, G-5b is a promising long-acting SERD worthy of further investigation and optimization.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Karoline B. Waitman, Larissa C. de Almeida, Marina C. Primi, Jorge A. E. G. Carlos, Claudia Ruiz, Thales Kronenberger, Stefan Laufer, Marcia Ines Goettert, Antti Poso, Sandra V. Vassiliades, Vinicius A. M. de Souza, Monica F. Z. J. Toledo, Neuza M. A. Hassimotto, Michael D. Cameron, Thomas D. Bannister, Leticia Costa-Lotufo, Joa o A. Machado-Neto, Mauricio T. Tavares, Roberto Parise-Filho
Summary: A series of hybrid inhibitors combining pharmacophores of known kinase inhibitors and benzohydroxamate HDAC inhibitors were synthesized and evaluated for their anticancer activity and pharmacokinetic properties. Compounds 4d-f exhibited promising cytotoxicity against hematological cells and moderate activity against solid tumor models. Compound 4d showed potent inhibition of multiple kinase targets and had stable interactions with HDAC and members of the JAK family. These compounds showed selective cytotoxicity with minimal effects on non-tumorigenic cells and favorable pharmacokinetic profiles.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Michal Sulik, Diana Fontinha, Dietmar Steverding, Szymon Sobczak, Michal Antoszczak, Miguel Prudencio, Adam Huczynski
Summary: This study describes the synthesis of the first-in-class ivermectin derivatives obtained through derivatization of the C13 position, along with the unexpected rearrangement of the macrolide ring. These derivatives show potential for antiparasitic activity and are important for the development of new antiparasitic agents.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Jun Liu, Qiu-Xian Chen, Wen-Fu Wu, Dong Wang, Si -Yu Zhao, Jia-Hao Li, Yi-Qun Chang, Shao-Gao Zeng, Jia-Yi Hu, Yu-Jie Li, Jia-Xin Du, Shu-Meng Jiao, Hai-Chuan Xiao, Qiang Zhang, Jun Xu, Jian-Fu Zhao, Hai -Bo Zhou, Yong-Heng Wang, Jian Zou, Ping-Hua Sun
Summary: A new anti-infective drug strategy has been discovered to attenuate virulence and modulate inflammation caused by drug-resistant Pseudomonas aeruginosa infections. Compound 5f inhibits biofilm formation, macrophage migration, and inflammatory response induced by P. aeruginosa, showing potential as a novel candidate against drug-resistant infections.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Liuzeng Chen, Ke Wang, Lingyun Wang, Wei Wang, Lifan Wang, Jia Li, Xiaohan Liu, Mengya Wang, Banfeng Ruan
Summary: In this study, a series of novel anti-inflammatory compounds were designed and synthesized based on the natural product pterostilbene skeleton. Among them, compound 8 showed the highest activity and exhibited its effects through inhibition of pro-inflammatory cytokines by blocking the NF-KB/MAPK signaling pathway. Compound 8 also demonstrated a good relieving effect on acute colitis in mice and showed good safety in acute toxicity experiments.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Si-Min Liang, Gui-Bin Liang, Hui-Ling Wang, Hong Jiang, Xian-Li Ma, Jian-Hua Wei, Ri-Zhen Huang, Ye Zhang
Summary: A series of novel multi-target antitumor agents were designed, synthesized, and evaluated. Some compounds exhibited significant antitumor activity and one compound showed excellent efficacy, limited toxicity, and low resistance. Further mechanism studies revealed that the compound exerted antitumor effects through multiple pathways.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
