Review
Oncology
Die Lv, Hongli Chen, Yun Feng, Bomiao Cui, Yingzhu Kang, Ping Zhang, Min Luo, Jiao Chen
Summary: The PKD family of serine-threonine kinases plays a significant role in various diseases, with small-molecule inhibitors emerging as alternative targeted therapy with fewer adverse effects. The successful development of PKD inhibitors could greatly impact cancer growth and the progression of other diseases.
FRONTIERS IN ONCOLOGY
(2021)
Article
Chemistry, Medicinal
Thomas Ihle Aarhus, Frithjof Bjornstad, Camilla Wolowczyk, Kristin Uhlving Larsen, Line Rognstad, Trygve Leithaug, Anke Unger, Peter Habenberger, Alexander Wolf, Geir Bjorkoy, Clare Pridans, Jan Eickhoff, Bert Klebl, Bard H. Hoff, Eirik Sundby
Summary: Colony-stimulating factor-1 receptor (CSF1R) is a receptor tyrosine kinase that can be inhibited for potential therapy in human disorders. Highly selective pyrrolo-[2,3-d]-pyrimidines were synthesized and developed in this study, showing subnanomolar enzymatic inhibition of CSF1R with excellent selectivity towards other kinases. The crystal structure analysis revealed the binding conformation of the protein, and the most promising compounds were evaluated for cellular potency, pharmacokinetic profiling, and in vivo stability, suggesting their relevance in disease treatment. Furthermore, these compounds primarily inhibited the autoinhibited form of the receptor, showing exquisite selectivity unlike pexidartinib.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Lixin Zhou, Tianyu Wang, Kuojun Zhang, Xiangyu Zhang, Sheng Jiang
Summary: Hematopoietic progenitor kinase 1 (HPK1) is a serine/threonine protein kinase that negatively regulates T cells, B cells, and dendritic cells-mediated immune responses. It plays a role in cellular processes such as immune cell activation, differentiation, proliferation, adhesion, and apoptosis. HPK1 is associated with the occurrence and development of human malignant tumors, making it a promising target for cancer immunotherapies.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Chemistry, Multidisciplinary
Adarsh Kumar, Kuber Kumar Bhagat, Ankit Kumar Singh, Harshwardhan Singh, Tanuja Angre, Amita Verma, Habibullah Khalilullah, Mariusz Jaremko, Abdul-Hamid Emwas, Pradeep Kumar
Summary: This study focuses on pyrido[2,3-d]pyrimidine derivatives as anticancer agents, which have emerged as a promising scaffold in medicinal chemistry with a broad spectrum of activities. The study covers the inhibition mechanisms, structure-activity relationship, and signaling pathways of these derivatives against various cancer targets. The review provides a comprehensive medicinal and pharmacological profile of pyrido[2,3-d]pyrimidines and offers insights for designing new selective, effective, and safe anticancer agents.
Article
Medicine, Research & Experimental
Ho Jin Lee, Phuong Chi Pham, Honglan Pei, Bumhee Lim, Seung Yeob Hyun, Byungyeob Baek, Byungjin Kim, Yunha Kim, Min-Hwan Kim, Nae-Won Kang, Hye-Young Min, Dae-Duk Kim, Jeeyeon Lee, Ho-Young Lee
Summary: The study revealed that LL6 is a novel IGF-1R/Src/AXL-targeting small molecule kinase inhibitor, showing inhibitory effects on non-small cell lung cancer cells, reducing tumor growth and metastasis with low toxicity.
Article
Multidisciplinary Sciences
Zhong Li, Anil Mathew Tharappel, Jimin Xu, Yuekun Lang, Cathleen M. Green, Jing Zhang, Qishan Lin, Sudha Chaturvedi, Jia Zhou, Marlene Belfort, Hongmin Li
Summary: A small-molecule library was screened to find potent inhibitors of the Cne Prp8 intein, leading to the identification of compound 6G-318S with potential antifungal properties. These inhibitors showed specific action against Cryptococcus species and demonstrated synergistic effects with certain antimycotics. Their binding to the target Prp8 intein was covalent and mutation of the active-site residue reduced binding, highlighting their potential as a new class of antifungal drugs.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Angeliki Ditsiou, Teresa Gagliano, Mark Samuels, Viviana Vella, Christos Tolias, Georgios Giamas
Summary: In the last decade, LMTK3 has been recognized as a key player in breast cancer and other types of cancers, with evidence showing its involvement in multiple signaling pathways. The identification of a potential LMTK3 inhibitor opens up new possibilities for developing novel cancer treatments based on the roles of LMTK3.
Review
Cell Biology
Ming He, Wenxing Lv, Yu Rao
Summary: PROTAC is a new technology for inducing protein degradation using small molecules, which shows advantages in overcoming tumor resistance, affecting non-enzymatic functions of target proteins, degrading undruggable targets, and providing rapid and reversible chemical knockout tools. However, it also faces challenges and issues as a rapidly developing new chemical biology technology.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Chemistry, Medicinal
Jiarui Hu, Dan Zhang, Keyue Tian, Changyu Ren, Heng Li, Congcong Lin, Xiaoli Huang, Jie Liu, Wuyu Mao, Jifa Zhang
Summary: Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein involved in various cellular processes and its hyperactivation leads to Parkinson's disease. Inhibiting LRRK2 is a promising therapeutic strategy for PD and recent studies have identified LRRK2 inhibitors with tissue specificity. Currently, there are four small-molecule LRRK2 inhibitors undergoing clinical trials. This review provides valuable information for the development of novel drugs targeting LRRK2.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Shi-Jie Hao, Ya-Xuan Zhu, Fu -Gen Wu
Summary: Researchers developed a membrane fusion liposome (MFL) loaded with a small-molecule tyrosine kinase inhibitor (TKI) and doxorubicin (Dox) to achieve tumor cell membrane fusion-mediated drug delivery and enhanced chemotherapy of drug-resistant tumor.
JOURNAL OF CONTROLLED RELEASE
(2023)
Review
Pharmacology & Pharmacy
Tingting Jiang, Guan Wang, Yao Liu, Lu Feng, Meng Wang, Jie Liu, Yi Chen, Liang Ouyang
Summary: TRKA, TRKB, and TRKC are important members of the cell surface receptor tyrosine kinase family, regulating cell proliferation, differentiation, and apoptosis. NTRK gene fusions act as oncogenic drivers for a variety of tumors, making TRK inhibitors promising targets for anti-tumor therapy.
ACTA PHARMACEUTICA SINICA B
(2021)
Review
Oncology
Wenda Huang, Zhaonian Hao, Feng Mao, Dongsheng Guo
Summary: Glioblastoma, the most common primary malignant brain tumor, is characterized by alterations in genes and proteins that play crucial roles in its pathogenesis. Small molecule inhibitors have shown efficacy in clinical trials for hematologic cancers and some solid tumors, with studies in glioblastoma showing noninferiority in progressive cases compared to historical outcomes. However, dosing regimens should be carefully considered in future clinical trials to avoid clinical inferiority.
FRONTIERS IN ONCOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Andrew R. Conery, Jennifer L. Rocnik, Patrick Trojer
Summary: The approval of the first histone methyltransferase inhibitor in 2020 marks a significant milestone in the field of targeted manipulation of chromatin regulatory pathways for cancer treatment. Despite the complexity of identifying key targets for therapeutic intervention, approaches in chemical biology have played a critical role in discovering key nodes in these pathways and translating them into potential cancer therapies. This review highlights the importance of chemical probes, drug candidates, and translational strategies in maximizing the impact of epigenetic writer enzymes in cancer therapy.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Fiachra Humphries, Liraz Shmuel-Galia, Zhaozhao Jiang, Jeffrey Y. Zhou, Leonard Barasa, Santanu Mondal, Ruth Wilson, Nadia Sultana, Scott A. Shaffer, Sze -Ling Ng, G. Scott Pesiridis, Paul R. Thompson, Katherine A. Fitzgerald
Summary: The article discusses the discovery of a potent small-molecule inhibitor of STING, which can effectively block STING signaling and the production of inflammatory responses. This discovery highlights the potential for using this inhibitor in the treatment of STING-driven inflammatory diseases.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Oncology
Javier Bregante, Anna Schoenbichler, Daniel Poeloeske, Lina Degenfeld-Schonburg, Garazi Monzo Contreras, Emir Hadzijusufovic, Elvin D. de Araujo, Peter Valent, Richard Moriggl, Anna Orlova
Summary: FLT3-ITD mutations are common and detrimental in AML, with AML cells quickly developing resistance to FLT3 kinase inhibitors. Through a drug screen, new potential therapeutics like ispinesib, WS6, ponatinib, and cabozantinib have been identified for FLT3-ITD+ AML. Combination therapy with cabozantinib and ispinesib shows strong efficacy against FLT3-ITD+ AML, suggesting promising novel treatment options for this clinical challenge.
Article
Pediatrics
Chhinder P. Sodhi, Peter Wipf, Yukihiro Yamaguchi, William B. Fulton, Mark Kovler, Diego F. Nino, Qinjie Zhou, Emilyn Banfield, Adam D. Werts, Mitchell R. Ladd, Rachael H. Buck, Karen C. Goehring, Thomas Prindle, Sanxia Wang, Hongpeng Jia, Peng Lu, David J. Hackam
Summary: The study showed that human milk oligosaccharides 2'-FL and 6'-SL can prevent NEC through inhibition of TLR4 signaling, while lactose cannot. The results indicate that these HMOs reduced NEC occurrence in mouse and piglet models.
PEDIATRIC RESEARCH
(2021)
Article
Endocrinology & Metabolism
Nicolas Manzke Glanzel, Mateus Grings, Nevton Teixeira da Rosa-Junior, Leila Maria Cereta de Carvalho, Al-Walid Mohsen, Peter Wipf, Moacir Wajner, Jerry Vockley, Guilhian Leipnitz
Summary: Sulfite oxidase (SO) deficiency causes tissue sulfite accumulation and patients present with seizures and neurological damage. Treatment is mainly supportive. Study shows that treatment with JP4-039 can prevent or attenuate oxidative stress and apoptosis induced by sulfite injection.
JOURNAL OF INHERITED METABOLIC DISEASE
(2021)
Article
Pediatrics
Chhinder P. Sodhi, Peter Wipf, Yukihiro Yamaguchi, William B. Fulton, Mark Kovler, Diego F. Nino, Qinjie Zhou, Emilyn Banfield, Adam D. Werts, Mitchell R. Ladd, Rachael H. Buck, Karen C. Goehring, Thomas Prindle, Sanxia Wang, Hongpeng Jia, Peng Lu, David J. Hackam
PEDIATRIC RESEARCH
(2021)
Review
Chemistry, Organic
Thanh T. Nguyen, Peter Wipf
Summary: The development of intramolecular Diels-Alder cycloaddition of azole heterocycles has significantly impacted the efficient preparation of heterocyclic intermediates and natural products. While IMDAO reactions have been utilized as a key step in several synthetic schemes, IMDAI and IMDAT cycloadditions have been less studied. The review also highlights some drawbacks, such as the challenging preparation of IMDA precursors, and provides perspectives on expanding the transformations for target-directed syntheses.
SYNTHESIS-STUTTGART
(2021)
Article
Chemistry, Organic
Ettore J. Rastelli, Doris Yue, Caroline Millard, Peter Wipf
Summary: The polypropylene continuous-photoflow cell developed through 3D printing is cost-effective and suitable for photo-oxygenation reactions using ambient air as the sole co-reactant. It offers the benefits of scalability and a short residence time under blue LED light, which minimizes the formation of dark, insoluble decomposition products.
Article
Biochemistry & Molecular Biology
Yasaman Hamedani, Rayane Brinck Teixeira, Catherine Karbasiafshar, Peter Wipf, Sankha Bhowmick, M. Ruhul Abid
Summary: The study demonstrates that electrospinning methods can be utilized to load mitochondria-targeted antioxidants onto biocompatible nanofibrous scaffolds, preserving their antioxidant properties upon release and improving cell function.
Review
Clinical Neurology
Xuejing Zhang, Jaclyn Connelly, Edwin S. Levitan, Dandan Sun, Jane Q. Wang
Summary: Cerebrovascular disease, often leading to stroke, involves the multifunctional CaMKII protein. Past studies mainly focused on its role in neurons, but gaps remain in understanding how it functions in complex neurovascular processes. Emerging evidence suggests potential roles of CaMKII in the ischemic brain, sparking renewed research interest.
TRANSLATIONAL STROKE RESEARCH
(2021)
Article
Engineering, Chemical
Luiz Fernando Lepre, Stephane Sabelle, Floriane Beaumard, Ann Detroyer, Marie-Celine Frantz, Agilio Padua, Margarida Costa Gomes
Summary: This study utilized theoretical models to screen a series of promising ionic solvents-ionic liquids or eutectic mixtures for the dissolution of natural dyes. The research indicated that small ions with high charge density and capable of establishing strong hydrogen bonds are the best candidates for increasing the solubility of natural dyes.
INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
John S. Lazo, Elizabeth R. Sharlow, Robert Cornelison, Duncan J. Hart, Danielle C. Llaneza, Anna J. Mendelson, Ettore J. Rastelli, Nikhil R. Tasker, Charles N. Landen, Peter Wipf
Summary: High grade serous ovarian cancer often becomes drug resistant and recurrent. A study showed that high expression of Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3) is associated with poor patient survival in both early and late stages of ovarian cancer. A potent allosteric small molecule PTP4A3 inhibitor, JMS-053, was found to reduce high grade serous ovarian cancer cell survival. Results also showed that controlling PTP4A3 can affect cell migration and the inhibitor JMS-053 can lead to reduced cell migration.
Article
Biochemistry & Molecular Biology
Keishla M. Rodriguez-Graciani, Xavier R. Chapa-Dubocq, Esteban J. Ayala-Arroyo, Ivana Chaves-Negron, Sehwan Jang, Nataliya Chorna, Taber S. Maskrey, Peter Wipf, Sabzali Javadov
Summary: In this study, the metabolome of H9c2 cardioblasts during RSL3-induced ferroptosis was elucidated using gas chromatography-mass spectrometry. The results showed that RSL3 decreased the levels of amino acids involved in glutathione synthesis and increased the levels of saturated fatty acids. RSL3 also significantly altered the levels of mitochondrial tricarboxylic acid cycle intermediates. Furthermore, ferrostatin-1, XJB-5-131, and TSM-1005-44 protected against RSL3-induced cell death and preserved the metabolomic profile of the cells.
Review
Biochemistry & Molecular Biology
Marie-Celine Frantz, Roger Rozot, Laurent Marrot
Summary: The skin, being the interface between the body and the external environment, is highly susceptible to the impact of the exposome. Nrf2-controlled pathways play a crucial role in adapting to the stresses caused by the exposome, and modulation of Nrf2 in the skin could be a strategy for skin protection and care.
Article
Chemistry, Medicinal
Qiming Jane Wang, Peter Wipf
Summary: Research on the three isoforms of protein kinase D (PKD1, PKD2, and PKD3) has matured over the past three decades. Medicinal chemistry has provided a diverse set of active site inhibitors, but they have not been tested in clinical trials yet. There is a need for potent and selective PKD modulators to address unresolved medical needs in various diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Medicine, Research & Experimental
Liping Chen, Jinjun Zhao, Yapeng Chao, Adhiraj Roy, Wenjing Guo, Jiabi Qian, Wanfu Xu, Robyn T. Domsic, Robert Lafyatis, Binfeng Lu, Fan Deng, Q. Jane Wang
Summary: In this study, the researchers investigated the role of protein kinase D2 (PKD2) in inflammation-induced dermal fibrosis. They found that PKD2 promotes dermal fibrosis by regulating immune cell infiltration, cytokine production, and downstream activation of Akt in lesional skin. Genetic ablation or pharmacologic inhibition of PKD2 activity significantly blocked inflammation-induced dermal fibrosis, suggesting that PKD2 may be a potential therapeutic target for this condition.
LABORATORY INVESTIGATION
(2023)
Article
Biochemistry & Molecular Biology
Merlin Airik, Haley Arbore, Elizabeth Childs, Amy B. Huynh, Yu Leng Phua, Chi Wei Chen, Katherine Aird, Sivakama Bharathi, Bob Zhang, Peter Conlon, Stanislav Kmoch, Kendrah Kidd, Anthony J. Bleyer, Jerry Vockley, Eric Goetzman, Peter Wipf, Rannar Airik
Summary: Karyomegalic interstitial nephritis (KIN) is a genetic kidney disease caused by recessive mutations in the FAN1 DNA repair enzyme. The disease is characterized by genomic instability and mitotic abnormalities in tubular epithelial cells. Hypersensitivity to endogenous reactive oxygen species (ROS) is identified as a key factor in the pathogenesis of KIN, leading to chronic oxidative and double-strand DNA damage.
Article
Neurosciences
Jaclyn A. Connelly, Xuejing Zhang, Yuzhou Chen, Yapeng Chao, Yejie Shi, Tija C. Jacob, Q. Jane Wang
Summary: Ischemic stroke, a leading cause of death and disability in adults, requires the discovery of new targets and therapies. This study reveals an upregulation of PKD2 expression and activity in the brain and primary neurons during ischemic stroke, suggesting a potential role in neuronal survival. Deactivation of PKD2 worsened stroke outcomes in mice, indicating a neuroprotective function. AKT and CREB were identified as main signaling pathways regulated by PKD2 for neuronal survival during ischemia/reperfusion injury.
NEUROBIOLOGY OF DISEASE
(2023)
