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
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
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
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)
Article
Oncology
Mingyue Liu, Chang Xu, Xiaochun Qin, Wenwu Liu, Deping Li, Hui Jia, Xudong Gao, Yuting Wu, Qiong Wu, Xiangbo Xu, Bo Xing, Xiaowen Jiang, Hongyuan Lu, Yingshi Zhang, Huaiwei Ding, Qingchun Zhao
Summary: This study investigated a novel P-gp inhibitor DHW-221 and its effects on non-small cell lung cancer (NSCLC) cells. DHW-221 exhibited antiproliferative activity, suppressed cell migration and invasion, and overcame resistance to paclitaxel by inhibiting P-gp. Furthermore, DHW-221 induced FOXO3a nuclear translocation via Akt inhibition, leading to mitochondrial apoptosis and G0/G1 cell cycle arrest.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Ewa Zeslawska, Waldemar Tejchman, Annamaria Kincses, Gabriella Spengler, Wojciech Nitek, Grzegorz Zuchowski, Ewa Szymanska
Summary: Multidrug resistance (MDR) is a major reason for the failure of anticancer and antiviral chemotherapies. In this study, a series of newly synthesized 5-arylidenerhodanines were investigated for their ability to inhibit the ABCB1 efflux pump in mouse T-lymphoma cancer cells. Compounds with a triphenylamine moiety and the carboxyl group showed strong inhibitory effects, with over 17-fold higher potency than verapamil. The cytotoxic and antiproliferative effects of these compounds on T-lymphoma cells were also examined.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
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)
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
Biochemistry & Molecular Biology
Tingting Zou, Cheng Zeng, Junyan Qu, Xiaohua Yan, Zhenghong Lin
Summary: The study reveals that rutaecarpine can reverse ABCB1-mediated multidrug resistance by promoting the degradation of ABCB1 protein through increasing the protein level of MARCH8. This approach of co-administering rutaecarpine with conventional chemotherapeutic agents shows therapeutic effects on transplanted tumors.
Review
Pharmacology & Pharmacy
Jinyun Dong, Li Yuan, Can Hu, Xiangdong Cheng, Jiang -Jiang Qin
Summary: Multidrug resistance (MDR) is a major threat in chemotherapy, and the overexpression of ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp)/ABCB1, plays a role in MDR. Targeting P-gp with small molecule inhibitors is an effective approach, but no clinically useful inhibitors have been identified so far. Therefore, further research is needed to overcome MDR.
PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Biochemistry & Molecular Biology
Ashutosh Singh, Sandesh Kumar Patel, Prateek Kumar, Kanhu Charan Das, Deepanshu Verma, Rohit Sharma, Timir Tripathi, Rajanish Giri, Natalia Martins, Neha Garg
Summary: The resistance of cancer cells to chemotherapy is a major challenge in drug discovery. P-glycoprotein (P-gp) overexpression is directly linked to multidrug resistance (MDR) in cancer cells. Quercetin has been reported to inhibit the activity of P-gp, but the underlying mechanism is not fully understood. This study reveals the mechanistic understanding of quercetin-induced modulation of P-gp using molecular docking and molecular dynamics simulation.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
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
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)
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
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)
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)