Review
Oncology
Soudeh Ghafouri-Fard, Tayyebeh Khoshbakht, Bashdar Mahmud Hussen, Peixin Dong, Nikolaus Gassler, Mohammad Taheri, Aria Baniahmad, Nader Akbari Dilmaghani
Summary: This article summarizes the important role of Cyclin-dependent kinases (CDK) in cancer, emphasizing the significance of understanding CDK function and mechanisms for future cancer therapies targeting these kinases.
CANCER CELL INTERNATIONAL
(2022)
Article
Chemistry, Inorganic & Nuclear
Ruilin Guan, Lina Xie, Lili Wang, Ying Zhou, Yu Chen, Liangnian Ji, Hui Chao
Summary: NecroIr1 and NecroIr2, iridium(iii) complexes, induce necroptosis in cisplatin-resistant lung cancer cells by selectively accumulating in mitochondria and causing oxidative stress. Additionally, they interfere with cell cycle progression, leading to G0/G1 phase arrest. The combined effect of necroptosis induction and cell cycle arrest makes them potential antitumor agents against drug-resistant cancer cells.
INORGANIC CHEMISTRY FRONTIERS
(2021)
Review
Oncology
Mitra Zabihi, Ramin Lotfi, Amir-Mohammad Yousefi, Davood Bashash
Summary: CDKs, cyclins, and CKIs play important roles in the cell cycle regulatory machinery, and dysregulation of their expression or function can contribute to tumorigenesis. While designing CDK inhibitors to target tumor cells shows promise, the non-canonical functions of CDKs pose challenges in their application. This review aims to explore the biology of CDKs and their contribution to tumorigenesis, and discuss the pros and cons of CDK inhibition in the treatment of human cancers.
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Aadil Javed, Mahdieh Yarmohammadi, Kemal Sami Korkmaz, Teresa Rubio-Tomas
Summary: Gastric cancer is characterized by uncontrolled growth and metastasis of gastric epithelial cells, which is predominantly in adenocarcinoma form. The regulation of gastric cell growth is influenced by key cell cycle regulators, including Cyclins and Cyclin-dependent kinases (CDKs). Dysregulation of these molecules can lead to disturbances in cell cycle dynamics and the development of gastric cancer. Numerous studies have examined the roles of Cyclins and CDKs in gastric cancer, and this review aims to compile evidence of upstream regulators that activate or inhibit Cyclins and CDKs. It serves as a comprehensive resource for future studies and hypothesis generation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Xochitl Morales-de la Cruz, Alejandra Mandujano-Chavez, Daniel R. Browne, Timothy P. Devarenne, Lino Sanchez-Segura, Mercedes G. Lopez, Edmundo Lozoya-Gloria
Summary: Botryococcus braunii produces liquid hydrocarbons that can be processed into combustion engine fuels, but its slow cell growth rate and differences in cell cycle and division processes exist between different races of the algae.
Review
Chemistry, Medicinal
Sonal M. Manohar
Summary: This article reviews cyclin-dependent kinases as potential targets for colorectal cancer (CRC) and discusses therapeutic candidates to target CDKs.
FUTURE MEDICINAL CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Marzena Staniszewska, Kajetan Kielbowski, Klaudia Rusinska, Estera Bakinowska, Ewa Gromowska, Andrzej Pawlik
Summary: In this review, the potential of cyclin-dependent kinases (CDK) as novel therapeutic targets in rheumatoid arthritis (RA) and psoriasis is evaluated. CDK inhibitors show promise due to their potential multidirectional effects on osteoclastogenesis, neutrophil apoptosis, and macrophage apoptosis, all of which play important roles in the development of joint destruction and inflammation in RA and psoriasis. However, further clinical trials are needed to assess the efficacy and safety of CDK-blocking therapy in these conditions.
EXPERT OPINION ON THERAPEUTIC TARGETS
(2023)
Article
Anatomy & Morphology
Xiqin Ruan, Jun Jiang
Summary: This study revealed that RACGAP1 is overexpressed in cervical cancer and its downregulation inhibits cell proliferation and cell cycle progression in cervical cancer cells through regulating CDC25C expression.
Article
Chemistry, Medicinal
Weijiao Chen, Minghui Ji, Hao Cheng, Mingming Zheng, Fei Xia, Wenjian Min, Huanaoyu Yang, Xiao Wang, Liping Wang, Lijuan Cao, Kai Yuan, Peng Yang
Summary: Breast cancer is the most common tumor in women, and selective CDK4/6 inhibitors play an important role in its treatment. In this study, a highly selective CDK4/6 inhibitor was discovered through virtual screening and structural optimization. It exhibited excellent safety profiles and efficacy, making it a great candidate for preclinical studies of breast cancer.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Shinya Matsuda, Ushio Kikkawa, Akio Nakashima
Summary: Our study demonstrates the essential role of Pef1 in promoting pre-meiotic DNA replication and regulating meiotic initiation and progression through cyclin-coordinated mechanisms. Deletion of pef1 leads to defects in meiotic nuclear divisions, suppressed expression of DNA replication factors, and delayed meiotic progression, highlighting the importance of Pef1 in meiosis.
Review
Oncology
Alessandra Merlini, Valeria Pavese, Giulia Manessi, Martina Rabino, Francesco Tolomeo, Sandra Aliberti, Lorenzo D'Ambrosio, Giovanni Grignani
Summary: Effective treatment of advanced/metastatic bone and soft tissue sarcomas remains a medical challenge. CDK inhibitors have shown potential therapeutic effects in various cancer types, including sarcomas. This review explores the molecular basis and therapeutic implications of CDK inhibitors in sarcoma treatment and discusses the possibility of combination therapies with conventional treatments, targeted therapy, and immunotherapy to integrate CDK inhibition in sarcoma treatment.
FRONTIERS IN ONCOLOGY
(2023)
Review
Oncology
Edward C. Dominguez, Carly Roleder, Brian Ball, Alexey V. Danilov
Summary: Targeting CDK9 in lymphoid malignancies shows promise in inducing apoptosis by inhibiting mRNA transcription. Early clinical trials have demonstrated the safety of CDK9 inhibitors, although further research is needed to confirm their efficacy.
LEUKEMIA & LYMPHOMA
(2023)
Article
Biochemistry & Molecular Biology
Susan Kelso, Siobhan O'Brien, Igor Kurinov, Stephane Angers, Frank Sicheri
Summary: CDK11 is a kinase that controls cell proliferation by regulating transcription, RNA splicing, and the cell cycle. OTS964 is a small-molecule inhibitor that shows specificity for CDK11 in cells. The crystal structure analysis reveals that CDK11 adopts an active-like conformation when bound to OTS964. The contribution of specific amino acids to the binding of OTS964 to CDK11 was evaluated by in vitro isothermal titration calorimetry (ITC) and resistance studies in cells.
Article
Biochemistry & Molecular Biology
Azlann Arnett, Keagan G. Moo, Kaitlin J. Flynn, Thomas B. Sundberg, Liv Johannessen, Alykhan F. Shamji, Nathanael S. Gray, Thomas Decker, Ye Zheng, Vivian H. Gersuk, Ziaur S. Rahman, David E. Levy, Isabelle J. Marie, Peter S. Linsley, Ramnik J. Xavier, Bernard Khor
Summary: The CDK8 inhibitor DCA exerts a unique tolerogenic profile in immune cells, promoting Treg and Th2 differentiation while inhibiting Th1 and Th17 differentiation. Mechanistic studies have shown that DCA promotes Treg differentiation by regulating the CDK8-GATA3-FOXP3 pathway.
MOLECULAR AND CELLULAR BIOLOGY
(2021)
Article
Oncology
Shuanggang Chen, Binyan Shen, Ying Wu, Lujun Shen, Han Qi, Fei Cao, Tao Huang, Hongtong Tan, Guoping Zhang, Weijun Fan
Summary: This study suggests that CDK1 and CDK4 may serve as potential prognostic biomarkers for hepatocellular carcinoma (HCC). The high expression of CDK1 and CDK4 is significantly associated with worse prognosis in HCC patients. The study also identifies transcription factors and immune cell-related markers that are correlated with CDK1 and CDK4 expression. Targeting these transcription factors combined with immunotherapy may be a promising therapeutic strategy for HCC patients with high CDK1 and CDK4 expression, especially those with hepatitis-related HCC.
JOURNAL OF CANCER RESEARCH AND THERAPEUTICS
(2023)
Article
Microbiology
Marta L. Lima, Lindsay B. Tulloch, Victoriano Corpas-Lopez, Sandra Carvalho, Richard J. Wall, Rachel Milne, Eva Rico, Stephen Patterson, Ian H. Gilbert, Sonia Moniz, Lorna MacLean, Leah S. Torrie, Carmine Morgillo, David Horn, Fabio Zuccotto, Susan Wyllie
Summary: Phenotypic screening has identified a potential compound for treating Chagas' disease caused by Trypanosoma cruzi. Further studies have revealed the compound's primary target and identified potential secondary targets. These findings provide new insights for the discovery of anti-Chagas drugs.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Obstetrics & Gynecology
Franz S. Gruber, Zoe C. Johnston, Neil R. Norcross, Irene Georgiou, Caroline Wilson, Kevin D. Read, Ian H. Gilbert, Jason R. Swedlow, Sarah Martins da Silva, Christopher L. R. Barratt
Summary: This study utilized a high-throughput screening platform to identify compounds that can enhance sperm motility, providing a promising starting point for male fertility drug discovery.
HUMAN REPRODUCTION
(2022)
Review
Developmental Biology
Zoe C. Johnston, Franz S. Gruber, Sean G. Brown, Neil R. Norcross, Jason Swedlow, Ian H. Gilbert, Christopher L. R. Barratt
Summary: Despite recent advances, there is still incomplete understanding of male infertility and male non-hormonal contraceptives. Direct observation of compounds' effects on sperm function can increase knowledge and advance the field.
Article
Microbiology
Fabio Tamaki, Fabio Fisher, Rachel Milne, Fernando Sanchez-Roman Teran, Natalie Wiedemar, Karolina Wrobel, Darren Edwards, Hella Baumann, Ian H. Gilbert, Beatriz Baragana, Jake Baum, Susan Wyllie
Summary: Artemisinin-based combination therapies have played a crucial role in reducing the global burden of malaria. However, the emergence of resistance in Southeast Asia and sub-Saharan Africa is now threatening their efficacy. Therefore, there is an urgent need to develop new antimalarials with diverse mechanisms of action.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Chemistry, Medicinal
Alasdair Smith, Richard J. Wall, Stephen Patterson, Tim Rowan, Eva Rico Vidal, Laste Stojanovski, Margaret Huggett, Shahienaz E. Hampton, Michael G. Thomas, Victoriano Corpas Lopez, Kirsten Gillingwater, Jeff Duke, Grant Napier, Rose Peter, Herve S. Vitouley, Justin R. Harrison, Rachel Milne, Laura Jeacock, Nicola Baker, Susan H. Davis, Frederick Simeons, Jennifer Riley, David Horn, Reto Brun, Fabio Zuccotto, Michael J. Witty, Susan Wyllie, Kevin D. Read, Ian H. Gilbert
Summary: African animal trypanosomiasis is a major problem in cattle and other livestocks in sub-Saharan Africa and current treatments are facing drug resistance. A medicinal chemistry program has developed a lead compound capable of curing cattle infected with two types of trypanosomes via intravenous dosing, with potential for further optimization to provide a single-dose intramuscular treatment for this disease.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Microbiology
Sarah Forrester, Amy Goundry, Bruna Torres Dias, Thyago Leal-Calvo, Milton Ozorio Moraes, Paul M. Kaye, Jeremy C. Mottram, Ana Paula C. A. Lima
Summary: This study used dual RNA-seq to investigate the transcriptional response of host and parasite in a mouse model of visceral leishmaniasis caused by Leishmania infantum and Leishmania donovani. The results showed that the host response was broadly similar in both infections, with around 10% of host differentially expressed genes varying between the two parasite species.
MICROBIOLOGY SPECTRUM
(2022)
Review
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
Summary: Leishmaniasis, Chagas disease, and human African trypanosomiasis are major causes of death and illness, particularly in low- and middle-income countries. The development of new medicines for leishmaniasis and Chagas disease is urgently needed, with limited progress in the clinical pipeline for Chagas disease. This review provides an overview of recent advances in understanding the biology of these pathogens, with a focus on drug discovery, as well as the development of new drug candidates and potential solutions to overcome challenges in clinical development.
NATURE REVIEWS MICROBIOLOGY
(2023)
Review
Parasitology
Mathieu Cayla, Y. Romina Nievas, Keith R. Matthews, Jeremy C. Mottram
Summary: Trypanosomatid parasitic protozoa have evolved unique mechanisms, such as protein kinases, to regulate their complex life cycles and adapt to different hosts, distinguishing them from other eukaryotes.
TRENDS IN PARASITOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Tatiana F. R. Costa, Amy Goundry, Alexandre Morrot, Dennis J. Grab, Jeremy C. Mottram, Ana Paula C. A. Lima
Summary: This study reveals the mechanism of Trypanosoma brucei rhodesiense penetration through the blood-brain barrier and causing sleeping sickness. The Cathepsin L-like cysteine peptidase and its endogenous inhibitor ICP play important roles in the infection process and regulate inflammatory responses. The results suggest that ICP helps to downregulate inflammatory responses and control the infection.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Microbiology
Francesca G. Tomasi, Jessica T. P. Schweber, Satoshi Kimura, Junhao Zhu, Laura A. T. Cleghorn, Susan H. Davis, Simon R. Green, Matthew K. Waldor, Eric J. Rubin
Summary: Peptidyl tRNA hydrolase (Pth) is essential for bacterial growth and contributes to the recycling of translation machinery. This study used a novel sequencing-based strategy called Cu-tRNAseq to investigate the physiological role of Pth in Mycobacterium tuberculosis (Mtb). The results showed that Pth is crucial for the turnover of peptidyl prolyl-tRNA and reducing its levels made Mtb more vulnerable to tRNA synthetase inhibitors and macrolides. These findings highlight the potential of targeting Pth as a new therapeutic approach for tuberculosis.
Article
Biology
Vincent Geoghegan, Juliana B. T. Carnielli, Nathaniel G. Jones, Manuel Saldivia, Sergios Antoniou, Charlotte Hughes, Rachel Neish, Adam Dowle, Jeremy C. Mottram
Summary: This study developed a new proximity biotinylation method to investigate the kinetochore of Leishmania parasites. By using this method, researchers identified novel kinetochore proteins and revealed the dynamic changes of the kinetochore during the parasite cell cycle. Additionally, the study uncovered the mechanism of action of a kinase inhibitor on the kinetochore, providing insights for finding new drug targets.
COMMUNICATIONS BIOLOGY
(2022)
Article
Chemistry, Medicinal
Laura A. T. Cleghorn, Richard J. Wall, Seibastien Albrecht, Stuart A. MacGowan, Suzanne Norval, Manu De Rycker, Andrew Woodland, Daniel Spinks, Stephen Thompson, Stephen Patterson, Victoriano Corpas Lopez, Gourav Dey, Iain T. Collie, Irene Hallyburton, Robert Kime, Frederick R. C. Simeons, Laste Stojanovski, Julie A. Frearson, Paul G. Wyatt, Kevin D. Read, Ian H. Gilbert, Susan Wyllie
Summary: Despite advancements in treatment options, there is a need for new drugs to eradicate human African trypanosomiasis (HAT). In this study, potent 2,4-diaminothiazoles were developed as drug-like inhibitors against Trypanosoma brucei. Animal testing confirmed the efficacy in the hemolymphatic stage, but optimization for brain penetration did not achieve the desired in vivo efficacy due to a shift in mechanism of action. Subsequent studies identified a nonessential kinase as the target and emphasized the importance of cytotoxic drugs for HAT treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Catherine N. Russell, Jennifer L. Carter, Juliet M. Borgia, Jacob Bush, Felix Calderon, Raquel Gabarro, Stuart J. Conway, Jeremy C. Mottram, Anthony J. Wilkinson, Nathaniel G. Jones
Summary: Leishmaniases are neglected tropical diseases caused by Leishmania parasites, and current treatments are limited. This study identifies bromodomains as a potential target for antileishmanial drug discovery and demonstrates that BDF5 bromodomains bind to human bromodomain inhibitors and exhibit activity against Leishmania promastigotes.
ACS INFECTIOUS DISEASES
(2023)
Review
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
Summary: Leishmaniasis, Chagas disease, and human African trypanosomiasis are causing significant death and morbidity, especially in low- and middle-income countries. There is a critical need for new medications for leishmaniasis and Chagas disease, while the clinical development pipeline for Chagas disease remains sparse. This review discusses recent advancements in understanding the biology of these pathogens, with a focus on drug discovery, and explores progress in developing new drug candidates and identifying potential molecular targets. The challenges in developing new clinical candidates are also discussed, along with potential solutions to overcome these hurdles.
NATURE REVIEWS MICROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Robert L. Summers, Charisse Flerida A. Pasaje, Joao P. Pisco, Josefine Striepen, Madeline R. Luth, Krittikorn Kumpornsin, Emma F. Carpenter, Justin T. Munro, De Lin, Andrew Plater, Avinash S. Punekar, Andrew M. Shepherd, Sharon M. Shepherd, Manu Vanaerschot, James M. Murithi, Kelly Rubiano, Asli Akidi, Sabine Ottilie, Nimisha Mittal, A. Hazel Dilmore, Madalyn Won, Rebecca E. K. Mandt, Kerry McGowen, Edward Owen, Chris Walpole, Manuel Llinas, Marcus C. S. Lee, Elizabeth A. Winzeler, David A. Fidock, Ian H. Gilbert, Dyann F. Wirth, Jacquin C. Niles, Beatriz Baragana, Amanda K. Lukens
Summary: In this study, we identified and validated the Plasmodium falciparum acetyl-coenzyme A synthetase (PfAcAS) as an important, druggable target. Genetic and chemical validation confirmed that mutations in PfAcAS confer resistance to two antiplasmodial compounds and that these compounds directly inhibit the enzyme. We also found that PfAcAS is essential for asexual growth and involved in the epigenetic regulation of gene expression.
CELL CHEMICAL BIOLOGY
(2022)
