Article
Chemistry, Medicinal
Yi Liu, Leilei Fu, Junhao Wu, Ming Liu, Guan Wang, Bo Liu, Lan Zhang
Summary: CDKs are key regulators of the cell cycle and have multiple functions, including interference with transcriptional events. Inhibiting the function of CDKs may serve as a potential strategy for cancer treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Sonal M. Manohar, Kalpana S. Joshi
Summary: The study found that the multitarget CDK inhibitor riviciclib has significant cytotoxic effects on CRC cells, inhibiting their clonogenic potential and inducing apoptosis. Combination of riviciclib with standard chemotherapeutic drugs showed synergy in CRC cells.
CURRENT MOLECULAR PHARMACOLOGY
(2022)
Review
Pharmacology & Pharmacy
Deep Rohan Chatterjee, Saumya Kapoor, Meenakshi Jain, Rudradip Das, Moumita Ghosh Chowdhury, Amit Shard
Summary: The development of proteolysis-targeting chimeras (PROTACs) has led to the discovery of drugs that specifically target undruggable proteins. Small molecule-based PROTACs that target intracellular pathways have entered clinical trials, and their combination with antibodies has shown potent effects in cancer treatment. This review discusses the recent milestones and challenges in this area of drug development, as well as the best path forward.
DRUG DISCOVERY TODAY
(2023)
Review
Pharmacology & Pharmacy
Oana-Maria Thoma, Markus F. Neurath, Maximilian J. Waldner
Summary: CDKs play a key role in cell cycle regulation, with aberrant expression potentially leading to cancer development. CDK inhibitors, such as CDK4/6 inhibitors, are being investigated as novel cancer therapies.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Prasenjit Mondal, Saswat Mohapatra, Debmalya Bhunia, Prabir Kumar Gharai, Nabanita Mukherjee, Varsha Gupta, Satyajit Ghosh, Surajit Ghosh
Summary: Cell proliferation is a crucial step that may lead to cancer if not properly regulated, with p16 protein often remaining inactive in cancer cells. Researchers have focused on restoring the activity of p16 protein using new viral vectors, small molecules, and peptides to control abnormal cell proliferation. By conjugating a nuclear-localized signal (NLS) sequence and a short peptide (AVPI), the efficiency of p16 peptide as an anti-leukemia therapeutic agent has been significantly enhanced.
RSC MEDICINAL CHEMISTRY
(2022)
Review
Chemistry, Medicinal
Daniel Schaefer, Xinlai Cheng
Summary: Despite the increasing number of biologics license applications, the development of covalent inhibitors remains a growing field in drug discovery. The successful approval of certain covalent protein kinase inhibitors and the recent discovery of covalent inhibitors for viral proteases represent advancements in covalent drug development. Covalent bonds targeting proteins offer advantages in target selectivity, drug resistance, and administration concentration. The electrophile (warhead) is a crucial factor for covalent inhibitors, dictating selectivity and reactivity, and can be modified through rational designs. Covalent inhibitors are also finding applications in protein degradation and targeting chimeras (PROTACs) for 'undruggable' proteins, as well as in the treatment of SARS-CoV-2.
Article
Chemistry, Medicinal
Hong-Yi Zhao, Hai-Peng Wang, Yu-Ze Mao, Hao Zhang, Minhang Xin, Xiao-Xiao Xi, Hao Lei, Shuai Mao, Dong-Hui Li, San-Qi Zhang
Summary: This study developed proteolysis targeting chimeras (PROTACs) targeting EGFR mutants by optimizing covalent EGFR ligands to overcome drug resistance in non-small-cell lung cancer (NSCLC). The covalent PROTAC CP17 was discovered to be a highly potent degrader against EGFRL858R/T790M and EGFRdel19 with excellent selectivity. Mechanism investigation showed that the lysosome was involved in the degradation process. Importantly, the covalent binding strategy was proven to be effective for designing PROTACs targeting EGFRL858R/T790M.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Oncology
Mengna Zhang, Lingxian Zhang, Ruoxuan Hei, Xiao Li, Haonan Cai, Xuan Wu, Qiping Zheng, Cheguo Cai
Summary: Dysregulated cell division is a key feature of cancer, and blocking cell division through CDK inhibitors (CDKIs) shows potential for cancer treatment. CDK4/6 inhibitors have been approved for metastatic breast cancer, but first-generation pan-CDK inhibitors have not been widely approved due to non-selectivity and toxicity. Efforts are being made to enable pan-CDK inhibitors for clinical application and combination therapy strategies have been developed to reduce toxicity and side effects.
AMERICAN JOURNAL OF CANCER RESEARCH
(2021)
Article
Chemistry, Medicinal
Yuan Zhao, Yuan-Yuan Guan, Fang Zhao, Tong Yu, Shao-Jie Zhang, Yi-Zhe Zhang, Ying-Chao Duan, Xiao-Li Zhou
Summary: The polycomb repressive complex 2 (PRC2) is an important epigenetic gene silencer, and its abnormal activity is closely related to tumor development and progression. Inhibitors targeting PRC2 have made progress, but limitations and drug resistance exist. Therefore, novel targeted therapy strategies for PRC2 have become a research focus.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Ni Made Pitri Susanti, Daryono Hadi Tjahjono
Summary: The cell cycle is crucial in cell development, and its progression is controlled by endogenous CDK inhibitors, CDKs, and cyclins. Dysregulation of the cell cycle can lead to cancer, making CDK a natural target for anticancer therapy. Understanding CDK structures and complexes with drugs helps in developing CDK inhibitors, from non-selective to selective CDK4/CDK6 inhibitors applied in clinical cancer treatment.
Review
Chemistry, Medicinal
Mohamed A. Said, Mohamed A. Abdelrahman, Mohammed A. S. Abourehab, Mohamed Fares, Wagdy M. Eldehna
Summary: Developing selective CDK2 inhibitors is challenging, but ongoing efforts by Incyte Corporation and Pfizer Inc. may bring novel information critical for the development of CDK2 inhibitors.
EXPERT OPINION ON THERAPEUTIC PATENTS
(2022)
Review
Pharmacology & Pharmacy
Jieqiong You, Ying Wang, Haifeng Chen, Fang Jin
Summary: As an essential mediator of inflammation and innate immunity, RIPK2 plays a significant role in transducing signaling downstream of NOD-like receptors, leading to the activation of pro-inflammatory cytokines. Its involvement in tumorigenesis and malignant progression suggests its potential as an anti-tumor drug target. This article evaluates the feasibility of targeting RIPK2 and summarizes the research progress of RIPK2 inhibitors. Furthermore, it analyzes the possibility of applying small molecule RIPK2 inhibitors in anti-tumor therapy.
FRONTIERS IN PHARMACOLOGY
(2023)
Review
Oncology
Xiao-Ru Liang, Yan-Fei Liu, Feng Chen, Zhi-Xia Zhou, Li-Jie Zhang, Zhi-Juan Lin
Summary: Long non-coding RNAs (lncRNAs) are involved in various biological processes and regulate key proteins in the cell cycle of cancer cells. Understanding their role in cell cycle regulation can lead to new therapeutic strategies for cancer treatment. This review article summarizes recent studies on lncRNA control of cell cycle-related proteins and discusses their emerging role in cancer diagnosis and therapy.
CANCER MANAGEMENT AND RESEARCH
(2023)
Review
Oncology
Abel Tesfaye Anshabo, Robert Milne, Shudong Wang, Hugo Albrecht
Summary: Cyclin-dependent kinases play a crucial role in cancer development, particularly in cell division and transcription. Dysregulation of the CDK9 pathway has been observed in various hematological and solid malignancies, making it a valuable anticancer target.
FRONTIERS IN ONCOLOGY
(2021)
Review
Oncology
Sandeep Rana, Jayapal Reddy Mallareddy, Sarbjit Singh, Lidia Boghean, Amarnath Natarajan
Summary: Cyclin-dependent kinases (CDKs) are important therapeutic targets in cancer treatment, but lack of selectivity and dose-limiting toxicities are challenges, alternative strategies like PROTACs and molecular glues have emerged. These new modalities utilize protein degradation machinery to modulate target protein function.
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)