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Bioorganic Chemistry Nov 2023Despite immune checkpoint inhibitors' tremendous success in the treatment of tumors, the moderate response rate limits their widespread use. Hematopoietic progenitor...
Despite immune checkpoint inhibitors' tremendous success in the treatment of tumors, the moderate response rate limits their widespread use. Hematopoietic progenitor kinase 1 (HPK1) is served as an essential negative regulator of T-cell receptor, which has been identified as a promising target for enhancing antitumor immunity. However, the development of a selective HPK1 inhibitor is still challenging. Herein, we reported a novel series of 1H-pyrazolo[3,4-d]pyrimidine derivatives as HPK1 inhibitors by structure-based rational design. The optimal compound 10n significantly inhibited HPK1 with an IC value of 29.0 nM and the phosphorylation of SLP76 at a concentration as low as 0.1 μM. Furthermore, compound 10n exhibited good selectivity over a panel of 25 kinases, including GLK from the same MAP4K family. Together, the current study provided a novel, potent, and selective HPK1 inhibitor, acting as a lead compound for the future development of cancer immunotherapy.
Topics: Protein Serine-Threonine Kinases; Phosphorylation; Antihypertensive Agents; Pyrimidines
PubMed: 37659145
DOI: 10.1016/j.bioorg.2023.106811 -
Molecular Cell Aug 2023A recent study by Yang et al. uncovers the pyrimidinosome, a multienzyme complex where enzymes from different subcellular compartments collaborate to enable efficient...
A recent study by Yang et al. uncovers the pyrimidinosome, a multienzyme complex where enzymes from different subcellular compartments collaborate to enable efficient pyrimidine biosynthesis and ferroptosis defense, highlighting the remarkable adaptability of cellular metabolism and new therapeutic opportunities.
Topics: Ferroptosis; Pyrimidines
PubMed: 37595553
DOI: 10.1016/j.molcel.2023.07.013 -
Chemical Society Reviews Mar 2024Epigenetic phenomena play a central role in cell regulatory processes and are important factors for understanding complex human disease. One of the best understood... (Review)
Review
Epigenetic phenomena play a central role in cell regulatory processes and are important factors for understanding complex human disease. One of the best understood epigenetic mechanisms is DNA methylation. In the mammalian genome, cytosines (C) in CpG dinucleotides were long known to undergo methylation at the 5-position of the pyrimidine ring (mC). Later it was found that mC can be oxidized to 5-hydroxymethylcytosine (hmC) or even further to 5-formylcytosine (fC) and to 5-carboxylcytosine (caC) by the action of 2-oxoglutarate-dependent dioxygenases of the TET family. These findings unveiled a long elusive mechanism of active DNA demethylation and bolstered a wave of studies in the area of epigenetic regulation in mammals. This review is dedicated to critical assessment of recent data on biochemical and chemical aspects of the formation and conversion of hmC in DNA, analytical techniques used for detection and mapping of this nucleobase in mammalian genomes as well as epigenetic roles of hmC in DNA replication, transcription, cell differentiation and human disease.
Topics: Animals; Humans; Epigenesis, Genetic; 5-Methylcytosine; Cytosine; DNA; Mammals
PubMed: 38205583
DOI: 10.1039/d3cs00858d -
Current Hematologic Malignancy Reports Jun 2024Summarize best practices for management of patients with early myelofibrosis (MF). (Review)
Review
PURPOSE OF REVIEW
Summarize best practices for management of patients with early myelofibrosis (MF).
RECENT FINDINGS
Myelofibrosis is a progressive myeloproliferative neoplasm (MPN) that generally produces burdensome symptoms and ultimately leads to worse overall survival than that observed in healthy controls or patients with other MPNs. Several Janus kinase inhibitors and various interferon formulations are now available for treatment of MF, with ruxolitinib notable for extending overall survival in addition to improving MF signs and symptoms. The chronic nature of the disease can lead some patients to avoid immediate treatment in favor of a watch-and-wait approach. This review summarizes the patient management approach taken in my practice, providing guidance and a discussion of best practices with an emphasis on the importance and clinical benefits of active treatment in early MF. In particular, a case is made to consider treatment with ruxolitinib for patients with intermediate-1 risk disease and to minimize delay between diagnosis and treatment initiation for patients with intermediate or high-risk disease.
Topics: Humans; Primary Myelofibrosis; Disease Management; Pyrazoles; Pyrimidines; Nitriles; Janus Kinase Inhibitors; Practice Guidelines as Topic
PubMed: 38441783
DOI: 10.1007/s11899-024-00729-8 -
Cancer Jul 2023
Topics: Humans; Child; Pyrimidines; Pyrimidinones; DNA Damage; Cell Cycle Proteins; Cell Line, Tumor; Protein-Tyrosine Kinases
PubMed: 37081596
DOI: 10.1002/cncr.34785 -
Future Medicinal Chemistry 2024Cancer as a devastating malignancy, seriously threatens human life and health, but most chemotherapeutics have long been criticized for unsatisfactory therapeutic... (Review)
Review
Cancer as a devastating malignancy, seriously threatens human life and health, but most chemotherapeutics have long been criticized for unsatisfactory therapeutic efficacy due to drug resistance and severe off-target toxicity. Pyrimidines, including fused pyrimidines, are privileged scaffolds for various biological cancer targets and are the most important class of metalloenzyme carbonic anhydrase inhibitors. Pyrimidine-sulfonamide hybrids can act on different targets in cancer cells simultaneously and possess potent activity against various cancers, revealing that hybridization of pyrimidine with sulfonamide is a promising approach to generate novel effective anticancer candidates. This review aims to summarize the recent progress of pyrimidine-sulfonamide hybrids with anticancer potential, covering papers published from 2020 to present, to facilitate further rational design of more effective candidates.
Topics: Humans; Sulfonamides; Pyrimidines; Antineoplastic Agents; Neoplasms; Carbonic Anhydrase Inhibitors; Molecular Structure; Animals
PubMed: 38624011
DOI: 10.4155/fmc-2024-0010 -
Journal of Medicinal Chemistry Nov 2023The breakthrough in drug development of KRAS inhibitors provides inspiration for targeting alternative KRAS mutations, especially the most prevalent KRAS variant. Based...
The breakthrough in drug development of KRAS inhibitors provides inspiration for targeting alternative KRAS mutations, especially the most prevalent KRAS variant. Based on the structural analysis of MRTX1133 in complex with KRAS, a comprehensive structure-activity study was conducted, which led to the discovery of several compounds (, , and ) that showed higher potency in suppressing the clonogenic growth of KRAS-dependent cancer cells. These new compounds markedly and selectively inhibited the binding of RBD peptide to GTP-bound KRAS with IC values between 0.48 and 1.21 nM. These new inhibitors were found to have dose-dependent anti-tumor efficacy in the AsPC-1 xenograft mouse models with a tumor growth inhibition of approximately 70% at a dose of 20 mg/kg twice daily (i.p.). Despite the non-optimal pharmacokinetic properties similar to those of MRTX1133, the high and potency of these new inhibitors call for further profiling.
Topics: Animals; Humans; Mice; Mutation; Proto-Oncogene Proteins p21(ras); Pyrimidines
PubMed: 37921024
DOI: 10.1021/acs.jmedchem.3c01724 -
The Journal of Biological Chemistry Dec 2023Cell proliferation requires metabolic reprogramming to accommodate biosynthesis of new cell components, and similar alterations occur in cancer cells. However, the...
Cell proliferation requires metabolic reprogramming to accommodate biosynthesis of new cell components, and similar alterations occur in cancer cells. However, the mechanisms linking the cell cycle machinery to metabolism are not well defined. Cyclin D1, along with its main partner cyclin-dependent kinase 4 (Cdk4), is a pivotal cell cycle regulator and driver oncogene that is overexpressed in many cancers. Here, we examine hepatocyte proliferation to define novel effects of cyclin D1 on biosynthetic metabolism. Metabolomic studies reveal that cyclin D1 broadly promotes biosynthetic pathways including glycolysis, the pentose phosphate pathway, and the purine and pyrimidine nucleotide synthesis in hepatocytes. Proteomic analyses demonstrate that overexpressed cyclin D1 binds to numerous metabolic enzymes including those involved in glycolysis and pyrimidine synthesis. In the glycolysis pathway, cyclin D1 activates aldolase and GAPDH, and these proteins are phosphorylated by cyclin D1/Cdk4 in vitro. De novo pyrimidine synthesis is particularly dependent on cyclin D1. Cyclin D1/Cdk4 phosphorylates the initial enzyme of this pathway, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), and metabolomic analysis indicates that cyclin D1 depletion markedly reduces the activity of this enzyme. Pharmacologic inhibition of Cdk4 along with the downstream pyrimidine synthesis enzyme dihydroorotate dehydrogenase synergistically inhibits proliferation and survival of hepatocellular carcinoma cells. These studies demonstrate that cyclin D1 promotes a broad network of biosynthetic pathways in hepatocytes, and this model may provide insights into potential metabolic vulnerabilities in cancer cells.
Topics: Biosynthetic Pathways; Cyclin D1; Cyclin-Dependent Kinase 4; Hepatocytes; Proteomics; Pyrimidines; Humans; Animals; Mice; Cell Line
PubMed: 38152849
DOI: 10.1016/j.jbc.2023.105407 -
The EMBO Journal Sep 2023Replication of the mitochondrial genome and expression of the genes it encodes both depend on a sufficient supply of nucleotides to mitochondria. Accordingly,...
Replication of the mitochondrial genome and expression of the genes it encodes both depend on a sufficient supply of nucleotides to mitochondria. Accordingly, dysregulated nucleotide metabolism not only destabilises the mitochondrial genome, but also affects its transcription. Here, we report that a mitochondrial nucleoside diphosphate kinase, NME6, supplies mitochondria with pyrimidine ribonucleotides that are necessary for the transcription of mitochondrial genes. Loss of NME6 function leads to the depletion of mitochondrial transcripts, as well as destabilisation of the electron transport chain and impaired oxidative phosphorylation. These deficiencies are rescued by an exogenous supply of pyrimidine ribonucleosides. Moreover, NME6 is required for the maintenance of mitochondrial DNA when the access to cytosolic pyrimidine deoxyribonucleotides is limited. Our results therefore reveal an important role for ribonucleotide salvage in mitochondrial gene expression.
Topics: Genes, Mitochondrial; Pyrimidines; Mitochondria; Nucleotides; DNA, Mitochondrial; Ribonucleotides
PubMed: 37439264
DOI: 10.15252/embj.2022113256 -
Inflammatory Bowel Diseases Mar 2024
Topics: Humans; Colitis, Ulcerative; Biological Products; Biological Factors; Pyrimidines; Piperidines
PubMed: 38142413
DOI: 10.1093/ibd/izad309