Article
Multidisciplinary Sciences
Caleb R. Glassman, Naotaka Tsutsumi, Robert A. Saxton, Patrick J. Lupardus, Kevin M. Jude, K. Christopher Garcia
Summary: Cytokines signal through cell surface receptor dimers to initiate activation of intracellular JAKs. This study reports the cryo-electron microscopy structure of JAK1 complexed with a cytokine receptor, and investigates the role of oncogenic JAK1 mutations in signaling.
Article
Oncology
Aaron T. Gerds
Summary: Mutations play a critical role in understanding the pathobiology of JAK/STAT activation in myeloproliferative neoplasms (MPNs), shaping the diagnostic classification, prognosis, and disease progression biology. Current research is focused on understanding the mechanisms of mutation occurrence and developing strategies to target them for disease management.
JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK
(2021)
Article
Biochemistry & Molecular Biology
Nikola Slaninova, Iveta Bryjova, Zenon Lasota, Radmila Richterova, Jan Kubicek, Martin Augustynek, Ayan Seal, Ondrej Krejcar, Antonino Proto
Summary: This work analyzes the research results on the genetic hematological risks associated with secondary polyglobulia. The study focuses on identifying key markers for diagnosing high-risk patients and excluding less important markers. The results can be used as clinical guidelines for diagnosing parameters with high sensitivity and specificity.
Article
Oncology
Pratibha Bhai, Benjamin Chin-Yee, Victor Pope, Ian Cheong, Maxim Matyashin, Michael A. Levy, Aidin Foroutan, Alan Stuart, Cyrus C. Hsia, Hanxin Lin, Bekim Sadikovic, Ian Chin-Yee
Summary: This study characterized the mutational landscape in patients referred for erythrocytosis using targeted next-generation sequencing. The findings revealed frequent mutations in genes such as TET2, DNMT3A, and ASXL1 in JAK2-positive patients, highlighting their implications for prognosis.
Review
Pharmacology & Pharmacy
Robert Roskoski
Summary: Janus kinase (JAK) family is a group of nonreceptor protein-tyrosine kinases that regulate mammalian cell signaling. They participate in multiple biological processes including inflammation, hematopoiesis, and immunity, together with various cytokines. Abnormal activation of JAKs is associated with inflammatory disorders and the development of different malignancies. Several JAK inhibitors have been developed and approved for the treatment of related diseases.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Chemistry, Multidisciplinary
Chaochao Xie, Guiying Xiao, Qianling Guo, Xiaoxue Wu, Guofu Zi, Wanjian Ding, Guohua Hou
Summary: A highly enantioselective rhodium-catalyzed reductive dearomatization of 7-substituted pyrazolo[1,5-a]pyrimidines has been achieved for the first time, yielding chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidines with excellent enantioselectivities up to 98% ee. This method also offers an efficient approach for the synthesis of the potent BTK inhibitor, zanubrutinib.
Article
Chemistry, Medicinal
Niklas G. Johansson, Loic Dreano, Keni Vidilaseris, Ayman Khattab, Jianing Liu, Arthur Lasbleiz, Orquidea Ribeiro, Alexandros Kiriazis, Gustav Boije af Gennas, Seppo Meri, Adrian Goldman, Jari Yli-Kauhaluoma, Henri Xhaard
Summary: Inhibition of membrane-bound pyrophosphatase (mPPase) with small molecules presents a new approach to combat pathogenic protozoan parasites, with identified compounds showing low micromolar inhibitory activities. Investigation of a new scaffold around pyrazolo[1,5-a]pyrimidine core revealed promising results in inhibiting Plasmodium falciparum mPPase and growth in ex vivo assays.
Article
Chemistry, Organic
Tian Sang, Chuntian Li, Fan Jia, Jing He, Yan Liu, Luigi Vaccaro, Jichang Liu, Ping Liu
Summary: This study has developed a series of halogenated systems for pyrazolo[1,5-a]pyrimidines, achieving selective transformations by mono- and di-iodination using varying ratios of pyrazolo[1,5-a]pyrimidines and NIS. Additionally, the reaction with NBS or NCS produces unique dibrominated or dichlorinated products. The wide range of substrates, good functional group tolerance, and gram-scale synthesis demonstrate the potential application of this reaction.
POLYCYCLIC AROMATIC COMPOUNDS
(2023)
Article
Chemistry, Organic
Sandra-L. Aranzazu, Alexis Tigreros, Andres Arias-Gomez, Jhon Zapata-Rivera, Jaime Portilla
Summary: An operably simple microwave-assisted BF3-mediated acetylation reaction of pyrazolo[1,5-a]pyrimidines has been reported. The synthesis of this essential building block is achieved in high yields using mild reaction conditions, inexpensive reagents, and even substrates with electron-deficient or highly hindered groups. The discovered acetylation method was successfully applied in other pi-excedent (N-hetero)aromatic substrates as well.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Hematology
Jan Stetka, Marc Usart, Lucia Kubovcakova, Shivam Rai, Tata Nageswara Rao, Joshua Sutter, Hui Hao-Shen, Stefan Dirnhofer, Florian Geier, Michael S. Bader, Jakob R. Passweg, Vania Manolova, Franz Durrenberger, Nouraiz Ahmed, Timm Schroeder, Tomas Ganz, Elizabeta Nemeth, Laura Silvestri, Antonella Nai, Clara Camaschella, Radek C. Skoda
Summary: JAK2-V617F mutation causes myeloproliferative neoplasms (MPNs) that manifest as polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis. Iron deficiency is already present in PV patients at diagnosis, while ET patients have normal iron stores. Mice models with JAK2-V617F mutation exhibit iron deficiency in the PV-like phenotype but normal iron stores in the ET-like phenotype. Alterations in iron availability mainly affect premegakaryocyte-erythrocyte progenitors in JAK2-mutant mice. Ferroportin inhibitors and minihepcidins show potential for treating PV patients.
Article
Chemistry, Multidisciplinary
Xuan Yang, Han Wee Ong, Rebekah J. Dickmander, Jeffery L. Smith, Jason W. Brown, William Tao, Edcon Chang, Nathaniel J. Moorman, Alison D. Axtman, Timothy M. Willson
Summary: During the development of analogues of 3-cyano-7-cyclopropylamino-pyrazolo[1,5-a]pyrimidines, it was discovered that phase II conjugation by GST enzymes played a major role in the metabolic transformation in hepatocytes. A protocol involving co-dosing with ethacrynic acid was developed to enhance the exposure of the analogues in mice.
Article
Chemistry, Organic
Wen-Qian Wu, Hua-Li Qin
Summary: A [3 + 2] cycloaddition reaction of N-amino pyridines, N-aminoquinolines, and N-aminoisoquinolines with 1-bromoethene-1-sulfonyl fluoride (BESF) was conducted to obtain pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]quinolinyl, and pyrazolo[5,1-a]isoquinolinyl sulfonyl fluorides with good yields (43-90%). This transformation process exhibits broad substrate specificity, mild reaction conditions, and operational simplicity. Therefore, it has significant value in the field of medicinal chemistry and other disciplines.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Runlai Liu, Shuai Zhang, Mingxin Huang, Zhenpeng Guo, Long Li, Mi Li, Lan Wu, Qi Guan, Weige Zhang
Summary: The newly designed compound 6d showed significant antiproliferative activity against MCF-7 cancer cells, inhibiting cancer cell growth and migration through multiple pathways.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Sherif M. H. Sanad, Alshimaa A. M. Abdelsalam, Aya A. Gamal Eldin, Esraa H. Abdelfattah, Fatma R. M. Hussein, Nada G. Mohammed, Nariman A. S. Taha, Ahmed E. M. Mekky
Summary: An efficient protocol was used to synthesize three new series of bis(pyrazolo[1,5-a]pyrimidines) linked to different spacers. The new compounds exhibited a wide range of antibacterial activity against six bacterial strains. The propane- and butane-linked bis(pyrazolo[1,5-a]pyrimidines) attached to 3-(4-methyl- or 4-methoxybenzyl) units showed the best antibacterial activity, with MIC and MBC values up to 2.5 and 5.1 µM, respectively. The previous compounds also demonstrated promising MurB inhibitory activity with IC50 values up to 7.2 µM.
CHEMISTRY & BIODIVERSITY
(2023)
Article
Hematology
Ruochen Jia, Thomas Balligand, Vasyl Atamanyuk, Harini Nivarthi, Erica Xu, Leon Kutzner, Jakob Weinzierl, Audrey Nedelec, Stefan Kubicek, Roman Lesyk, Oleh Zagrijtschuk, Stefan N. Constantinescu, Robert Kralovics
Summary: Targeting the GBD of CALR can inhibit the oncogenicity of mutant CALR, with specific compounds disrupting CALR-MPL interaction and inhibiting the JAK2-STAT5 pathway to selectively kill CALR-mutated cells.
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)