Editorial Material
Chemistry, Medicinal
Mark Klein
Summary: Cyclin-dependent kinases (CDKs) have important roles in normal cells and can be targeted for cancer therapy. CDK4 inhibitors have been approved for advanced breast cancer treatment. However, the development of selective inhibitors for individual CDKs is challenging due to the highly conserved ATP-binding site.
Review
Biochemistry & Molecular Biology
Marika A. V. Reinius, Elizabeth Smyth
Summary: The introduction of CKI inhibitors has been a major development in the treatment of advanced breast cancer, with potential applications beyond metastatic breast cancer treatment. Evidence suggests that these agents have impacts on cancer immunology and metabolism, expanding our understanding of their therapeutic effects. Challenges and opportunities in the 2020s, including treatment resistance and biomarker development, are anticipated in the continued research and application of CKIs.
EXPERT REVIEWS IN MOLECULAR MEDICINE
(2021)
Article
Oncology
Elena Garralda, Alison M. Schram, Philippe L. Bedard, Gary K. Schwartz, Eunice Yuen, Samuel C. McNeely, Silvia Ribeiro, Jason Cunningham, Yi Wang, Arantxa Urunuela, Xiaojian Xu, Patricia LoRusso
Summary: LY3405105 is a promising CDK7 inhibitor with good bioavailability and selectivity. However, the clinical trial showed limited efficacy and no plans for further development. The MTD of LY3405105 monotherapy was determined to be 20 mg QD.
Article
Plant Sciences
Rui-Yi Yang, Jia-Yi Tan, Zhe Liu, Xiao-Ling Shen, Ying-Jie Hu
Summary: The natural lignan LAF from Arctium lappa Linne has been found to inhibit tumor cell growth in vitro and in vivo. However, its role in cell cycle regulation remains unknown.
PHARMACEUTICAL BIOLOGY
(2023)
Article
Pharmacology & Pharmacy
Yanting Zhou, Xiandeng Li, Peifang Luo, Huiting Chen, Yan Zhou, Xueting Zheng, Yuan Yin, Haoche Wei, Hongji Liu, Wen Xia, Mingsong Shi, Xiaoan Li
Summary: CDK4/6 is a crucial player in various cancers and a potential target for anticancer drugs. The interaction between abemaciclib and human CDK6 was studied, and C2231-A was identified as a promising candidate compound with significant inhibitory effects on human breast cancer cell lines.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Lanlan Fu, Jiajia Mou, Yanru Deng, Xiaoliang Ren, Shuang Qiu
Summary: CDK1 plays an essential role in the cell cycle and has emerged as a new target for cancer therapy. A new series of flavone derivatives, including compound 2a, were discovered as potent CDK1 inhibitors. Compound 2a exhibited strong inhibitory activity against CDK1 and showed potential as a lead compound for CDK1 inhibitor development.
FRONTIERS IN CHEMISTRY
(2022)
Review
Chemistry, Medicinal
Marketa Kovalova, Joseph Peter Baraka, Vaclav Mik, Radek Jorda, Lei Luo, Hao Shao, Vladimir Krystof
Summary: CDK7 is a protein kinase that regulates the cell cycle and mRNA transcription, and it has emerged as a potential drug target in oncology. Six promising drug candidates have been evaluated in early clinical trials. This review analyzes patents published from 2018 to 2022 and provides an overview of CDK7 inhibitors as anticancer drugs, including their chemical structures, biochemical profiles, and developmental stages.
EXPERT OPINION ON THERAPEUTIC PATENTS
(2023)
Article
Cell Biology
Brian J. McHugh, Jillian Stephen, Calum T. Robb, Sarah Fox, Tiina Kipari, Jennifer A. Cartwright, Christopher Haslett, Rodger Duffin, Christopher D. Lucas, Adriano G. Rossi
Summary: Cyclin-dependent kinase inhibitor drugs can induce neutrophil apoptosis and enhance inflammation resolution. In this study, CDKi showed significant effects on macrophage pro-inflammatory mediator production and viability. Targeting CDK9 inhibited an inflammatory phenotype in human MDMs, suggesting its importance in therapeutically targeting pro-inflammatory macrophage functions during chronic inflammation.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Cell Biology
Kanta Yamazoe, Yoshihiro H. Inoue
Summary: The Cdk1-CycB complex is crucial for cell-cycle regulation. Import and export processes are important for the localization and activation of Cdk1. Interaction between Cdc25C and Cdk-activating kinase with Cdk1 in the nucleus is necessary for centrosome separation.
Article
Biochemistry & Molecular Biology
Jiajia Mou, Shuang Qiu, Danghui Chen, Yanru Deng, Teka Tekleab
Summary: The study reported a series of baicalein derivatives that significantly inhibited the proliferation of MCF-7 tumor cells and the activity of CDK1/cyclin B kinase. Among them, compound 4a showed better inhibition against MCF-7 proliferation, while compound 3o exhibited the best activity against CDK1/cyclin B kinase. These findings demonstrate that baicalein derivatives can be used as CDK1 inhibitors fighting against cancer.
CHEMICAL BIOLOGY & DRUG DESIGN
(2021)
Review
Pharmacology & Pharmacy
Kailin Li, Jieqiong You, Qian Wu, Wen Meng, Qiaojun He, Bo Yang, Chengliang Zhu, Ji Cao
Summary: Synthetic lethality is an effective antitumor strategy that has attracted great attention, with CDKs potentially serving as synthetic lethal factors when combined with certain oncogenes. This provides numerous antitumor treatment options and highlights the prospect of CDK inhibitors as antitumor compounds.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Oncology
David Howard, David James, Jezabel Garcia-Parra, Belen Pan-Castillo, Jenny Worthington, Nicole Williams, Zoe Coombes, Sophie Colleen Rees, Kerryn Lutchman-Singh, Lewis W. Francis, Paul Rees, Lavinia Margarit, R. Steven Conlan, Deyarina Gonzalez
Summary: Ovarian cancer is a deadly disease that is often diagnosed late, resulting in poor prognosis. Platinum-based therapies are commonly used, but resistance to these treatments is common, making prognosis even worse. This study aimed to evaluate the effectiveness of CDK inhibitors in platinum-resistant ovarian cancer models and their potential clinical utility. The results showed that the CDK inhibitor, dinaciclib, was highly effective in both cell lines and primary cells of ovarian cancer, even more so than cisplatin. Furthermore, resistance to cisplatin did not affect the sensitivity to dinaciclib, and the two drugs had an additive effect when used together. This suggests a potential role for pan-CDK inhibitors in the treatment of advanced and platinum-resistant ovarian cancer.
FRONTIERS IN ONCOLOGY
(2022)
Article
Microbiology
Juri Kim, Eun-Ah Park, Mee Young Shin, Soon-Jung Park
Summary: This study investigated the functional roles of Giardia lamblia CDKs (GlCDKs) and their cognate cyclins. Using morpholino-mediated knockdown and coimmunoprecipitation, the functions of GlCDK1 and GlCDK2 were distinguished. GlCDK1 with Glcyclin 3977 plays a crucial role in flagellum formation and cell cycle control of G. lamblia, while GlCDK2 with Glcyclin 22394/6584 is involved in cell cycle control.
MICROBIOLOGY SPECTRUM
(2023)
Review
Biochemistry & Molecular Biology
Pawel Lukasik, Michal Zaluski, Izabela Gutowska
Summary: Cyclin-dependent kinases are crucial in various cellular processes and their dysregulation can lead to diseases, making them potential drug targets.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Daniel J. Elson, Bach D. Nguyen, Rhand Wood, Yi Zhang, Veronica Puig-Sanvicens, Siva K. Kolluri
Summary: This study reveals a new regulatory cross-talk between p27(Kip1) and AhR, as p27(Kip1) interacts with AhR to negatively regulate AhR-mediated transcriptional responses. This adds to the existing knowledge that p27(Kip1) is a direct regulator of AhR transcription, providing a more comprehensive understanding of the regulatory interactions between p27(Kip1) and AhR.
Article
Chemistry, Medicinal
Kristyna Vlkova, Ruzena Padrtova, Tomas Gucky, Miroslav Perina, Eva Reznickova, Vladimir Krystof
Summary: We report a novel series of 3,5,7-trisubstituted pyrazolo[1,5-a]pyrimidines and their inhibitory activity on FLT3-ITD, CDK2, and CDK9. Compound 10b showed strong inhibition against all kinases and exhibited selectivity towards FLT3-ITD in MOLM13 and MV4-11 cell lines. Further analysis confirmed FLT3 as a cellular target of 10b through biochemical assays and molecular docking.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Biochemistry & Molecular Biology
Jana Bibova, Veronika Kabrtova, Veronika Vecerova, Zuzana Kucerova, Martin Hudecek, Lenka Plackova, Ondrej Novak, Miroslav Strnad, Ondrej Plihal
Summary: Plasmodiophora brassicae is a pathogen that causes clubroot disease in cruciferous plants, leading to morphological changes and symptoms such as gall formation and leaf abscission. The homeostasis of cytokinin and auxin appears to be crucial for club development. Study on late-stage infected Arabidopsis thaliana showed changes in cytokinin levels and their role in disease progression.
Article
Medicine, Research & Experimental
Marketa Kovalova, Libor Havlicek, Stefan Djukic, Jana Skerlova, Miroslav Perina, Tomas Pospisil, Eva Reznickova, Pavlina Rezacova, Radek Jorda, Vladimir Krystof
Summary: Targeting cyclin-dependent kinase 7 (CDK7) with a new trisubstituted pyrazolo[4,3-d]pyrimidine derivative, LGR6768, inhibits CDK7 in the nanomolar range and shows favorable selectivity across the CDK family. LGR6768 affects cell cycle regulation and transcription by inhibiting the phosphorylation of cell cycle CDKs and the carboxy-terminal domain of RNA polymerase II. It limits leukemia cell proliferation and induces apoptosis through changes in protein and mRNA levels related to CDK7 inhibition.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Review
Chemistry, Medicinal
Marketa Kovalova, Joseph Peter Baraka, Vaclav Mik, Radek Jorda, Lei Luo, Hao Shao, Vladimir Krystof
Summary: CDK7 is a protein kinase that regulates the cell cycle and mRNA transcription, and it has emerged as a potential drug target in oncology. Six promising drug candidates have been evaluated in early clinical trials. This review analyzes patents published from 2018 to 2022 and provides an overview of CDK7 inhibitors as anticancer drugs, including their chemical structures, biochemical profiles, and developmental stages.
EXPERT OPINION ON THERAPEUTIC PATENTS
(2023)
Article
Oncology
Hana Dostalova, Radek Jorda, Eva Reznickova, Vladimir Krystof
Summary: Small molecule Bruton's tyrosine kinase (BTK) inhibitors, including ibrutinib, have shown potential as effective treatments for haemato-oncological diseases. Recent studies have identified HER2 as an off-target kinase of BTK inhibitors, suggesting that these drugs may be repurposed for HER2-positive breast cancer. In this study, we investigated the anticancer effects of zanubrutinib, evobrutinib, tirabrutinib and acalabrutinib in different BCa cell lines and found that zanubrutinib effectively inhibits the HER2 signalling pathway and reduces cell proliferation. These findings support the potential use of zanubrutinib in HER2-amplified solid tumours.
INVESTIGATIONAL NEW DRUGS
(2023)
Article
Plant Sciences
Jaroslav Nisler, Zuzana Kucerova, Radoslav Koprna, Roman Sobotka, Jana Slivkova, Stephen Rossall, Martina Spundova, Alexandra Husickova, Jan Pilny, Danuse Tarkowska, Ondrej Novak, Maria Skrabisova, Miroslav Strnad
Summary: Increasing crop productivity and mitigating yield losses under stressful conditions are major challenges in agriculture. A recently discovered compound, MTU, delays senescence and enhances the growth of wheat plants. Multiyear field trials demonstrate that treatment with MTU increases average grain yields of wheat and barley by 5-8%. This compound acts independently of cytokinins or other phytohormones and appears to be the only chemical known to affect the stability and activity of PSI.
FRONTIERS IN PLANT SCIENCE
(2023)
Article
Chemistry, Medicinal
Urte Sachleviciute, Gabriel Gonzalez, Marie Kvasnicova, Sarka Stepankova, Neringa Kleiziene, Aurimas Bieliauskas, Marek Zatloukal, Miroslav Strnad, Frank A. Slok, Miroslav Kvasnica, Algirdas Sackus, Asta Zukauskaite
Summary: A library of 3-aryl-3-azetidinyl acetic acid methyl ester derivatives was synthesized and evaluated for neuroprotective activity in salsolinol- and glutamate-induced neurodegeneration models. Compound 28 showed the highest neuroprotective effect, which may be driven by reductions in oxidative stress and caspase-3/7 activity.
ARCHIV DER PHARMAZIE
(2023)
Article
Chemistry, Physical
Ab Majeed Ganai, Tabasum Khan Pathan, Sachin Balaso Mohite, Veronika Vojackova, Eva Reznickova, Karolina Kozlanska, Vladimir Krystof, Katya Govender, Sithabile Mokoena, Srinivas Reddy Merugu, Mahesh Palkar, Kimeshni Moodley, Rajshekhar Karpoormath
Summary: A series of novel 1,2,4-triazolo[4,3-b]pyridazine derivatives were designed and synthesized, with good to moderate yields. Spectroscopic studies (NMR and IR) confirmed the synthesis of the compounds, and the fluorine coupled 13C NMR data were explained. The compounds were tested for their in-vitro anti-proliferative activity against four human cancer cell lines, with compound 8l showing the most promising results.
JOURNAL OF MOLECULAR STRUCTURE
(2023)
Article
Biochemistry & Molecular Biology
Vaclav Mik, Tomas Pospisil, Federica Brunoni, Jiri Gruz, Vladimfra Nozkova, Claus Wasternack, Otto Miersch, Miroslav Strnad, Kristyna Flokova, Ondrej Novak, Jitka Siroka
Summary: This research presents a highly sensitive method for the reliable determination of seven OPDA-aa compounds in plants. The method was optimized for extraction, sample clean-up, and final analysis. Five endogenous (+)-OPDA-aa were identified and their levels were estimated in mechanically wounded Arabidopsis thaliana leaves, with a peak observed 60 minutes after the wounding. The synthetic and analytical methodologies developed in this study will contribute to the understanding of the biological significance of these metabolites in plants.
Article
Plant Sciences
Gabriel Gomez-Ocampo, Carlos D. Crocco, Jimena Cascales, Jana Oklestkova, Danuse Tarkowska, Miroslav Strnad, Santiago Mora-Garcia, Jose L. Pruneda-Paz, Miguel A. Blazquez, Javier F. Botto
Summary: B-Box-containing zinc finger transcription factor BBX21 inhibits hypocotyl elongation in Arabidopsis through the brassinosteroid pathway. It reduces sensitivity to synthetic active brassinosteroid 24-epiBL at low concentrations in simulated shade and represses the biosynthesis and signaling genes of brassinosteroids. BBX21 integrates brassinosteroid homeostasis and shade-light signaling to fine-tune hypocotyl elongation in Arabidopsis.
PLANT AND CELL PHYSIOLOGY
(2023)
Article
Plant Sciences
Vladimir Skalicky, Ioanna Antoniadi, Ales Pencik, Ivo Chamrad, Rene Lenobel, Martin F. Kubes, Marek Zatloukal, Asta Zukauskaite, Miroslav Strnad, Karin Ljung, Ondrej Novak
Summary: Auxin and cytokinin show subcellular distribution in Arabidopsis cells, forming hormone gradients. This finding provides important insights into the mechanisms of plant growth and development.
Article
Multidisciplinary Sciences
Lei Xia, Anastasia Komissarova, Arielle Jacover, Yehuda Shovman, Sebastian Arcila-Barrera, Sharona Tornovsky-Babeay, Milsee Mol Jaya Prakashan, Abdelmajeed Nasereddin, Inbar Plaschkes, Yuval Nevo, Idit Shiff, Oshri Yosefov-Levi, Tamara Izhiman, Eleonora Medvedev, Elad Eilon, Asaf Wilensky, Simon Yona, Oren Parnas
Summary: The study presents the application of HMPCITE-seq to identify gene combinations that improve innate immune cell function. Through CRISPR screening and high-order Perturb-Seq experiments, targeting Cebpb and Med12 is found to be more effective.
NATURE COMMUNICATIONS
(2023)
Article
Public, Environmental & Occupational Health
Suheir Ereqat, Mohammad Abdelhafez, Salam Iriqat, Qusai Ghaleb, Amjaad Abu Shams, Omar Abd Aldayem, Manal Ghattas, Abdelmajeed Nasereddin
Summary: The study found that the duration of diabetes and dyslipidemia were strong indicators for the progression of proliferative diabetic retinopathy (PDR), but the aldose reductase (ALR2) (C106T) polymorphism was not associated with the severity of diabetic retinopathy (DR).
HEALTH SCIENCE REPORTS
(2023)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
