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JCI Insight Apr 2024Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of undifferentiated myeloblasts, and agents that promote differentiation have been...
Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of undifferentiated myeloblasts, and agents that promote differentiation have been effective in this disease but are not curative. Dihydroorotate dehydrogenase inhibitors (DHODHi) have the ability to promote AML differentiation and target aberrant malignant myelopoiesis. We introduce HOSU-53, a DHODHi with significant monotherapy activity, which is further enhanced when combined with other standard-of-care therapeutics. We further discovered that DHODHi modulated surface expression of CD38 and CD47, prompting the evaluation of HOSU-53 combined with anti-CD38 and anti-CD47 therapies, where we identified a compelling curative potential in an aggressive AML model with CD47 targeting. Finally, we explored using plasma dihydroorotate (DHO) levels to monitor HOSU-53 safety and found that the level of DHO accumulation could predict HOSU-53 intolerability, suggesting the clinical use of plasma DHO to determine safe DHODHi doses. Collectively, our data support the clinical translation of HOSU-53 in AML, particularly to augment immune therapies. Potent DHODHi to date have been limited by their therapeutic index; however, we introduce pharmacodynamic monitoring to predict tolerability while preserving antitumor activity. We additionally suggest that DHODHi is effective at lower doses with select immune therapies, widening the therapeutic index.
Topics: Leukemia, Myeloid, Acute; Humans; Pyrimidines; Mice; Animals; Dihydroorotate Dehydrogenase; Immunotherapy; Cell Line, Tumor; Xenograft Model Antitumor Assays; Female
PubMed: 38646934
DOI: 10.1172/jci.insight.173646 -
Bioorganic & Medicinal Chemistry Feb 2017TAK1 (transforming growth factor-β-activated kinase 1) is an essential intracellular mediator of cytokine and growth factor signaling and a potential therapeutic target...
TAK1 (transforming growth factor-β-activated kinase 1) is an essential intracellular mediator of cytokine and growth factor signaling and a potential therapeutic target for the treatment of immune diseases and cancer. Herein we report development of a series of 2,4-disubstituted pyrimidine covalent TAK1 inhibitors that target Cys174, a residue immediately adjacent to the 'DFG-motif' of the kinase activation loop. Co-crystal structures of TAK1 with candidate compounds enabled iterative rounds of structure-based design and biological testing to arrive at optimized compounds. Lead compounds such as 2 and 10 showed greater than 10-fold biochemical selectivity for TAK1 over the closely related kinases MEK1 and ERK1 which possess an equivalently positioned cysteine residue. These compounds are smaller, more easily synthesized, and exhibit a different spectrum of kinase selectivity relative to previously reported macrocyclic natural product TAK1 inhibitors such as 5Z-7-oxozeanol.
Topics: Animals; Crystallography, X-Ray; Dose-Response Relationship, Drug; Humans; MAP Kinase Kinase Kinases; Mice; Microsomes, Liver; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors; Pyrimidines; Structure-Activity Relationship
PubMed: 28011204
DOI: 10.1016/j.bmc.2016.11.035 -
The EMBO Journal Feb 2009New experiments show that different combinations of translesion DNA polymerases act to bypass lesions in mammalian cells, depending on the type of DNA damage. Bypass of... (Review)
Review
New experiments show that different combinations of translesion DNA polymerases act to bypass lesions in mammalian cells, depending on the type of DNA damage. Bypass of most lesions tested was dependent on REV3L (pol zeta) and at least one additional DNA polymerase. The data fit a model whereby DNA polymerases work sequentially to bypass adducts in DNA.
Topics: Animals; Catalytic Domain; DNA; DNA Adducts; DNA Damage; DNA Primers; DNA Replication; DNA-Directed DNA Polymerase; Dimerization; Humans; Models, Biological; Pyrimidines; Saccharomyces cerevisiae; Ultraviolet Rays
PubMed: 19225445
DOI: 10.1038/emboj.2008.303 -
Angewandte Chemie (International Ed. in... Jun 2022Metabolic theories for the origin of life posit that inorganic catalysts enabled self-organized chemical precursors to the pathways of metabolism, including those that...
Metabolic theories for the origin of life posit that inorganic catalysts enabled self-organized chemical precursors to the pathways of metabolism, including those that make genetic molecules. Recently, experiments showing nonenzymatic versions of a number of core metabolic pathways have started to support this idea. However, experimental demonstrations of nonenzymatic reaction sequences along the de novo ribonucleotide biosynthesis pathways are limited. Here we show that all three reactions of pyrimidine nucleobase biosynthesis that convert aspartate to orotate proceed at 60 °C without photochemistry under aqueous conditions in the presence of metals such as Cu and Mn . Combining reactions into one-pot variants is also possible. Life may not have invented pyrimidine nucleobase biosynthesis from scratch, but simply refined existing nonenzymatic reaction channels. This work is a first step towards uniting metabolic theories of life's origin with those centered around genetic molecules.
Topics: Aspartic Acid; Pyrimidines
PubMed: 35304939
DOI: 10.1002/anie.202117211 -
Cell Host & Microbe Apr 2019In recent work, Whiteley et al. (2019) define a family of bacterial nucleotidyltransferases (CD-NTases) capable of synthesizing pyrimidine containing cyclic...
In recent work, Whiteley et al. (2019) define a family of bacterial nucleotidyltransferases (CD-NTases) capable of synthesizing pyrimidine containing cyclic dinucleotides and cyclic trinucleotides. CD-NTases are broadly distributed across bacterial phyla, suggesting that they play important roles in bacterial physiology and modulation of the metazoan host innate immune system.
Topics: Bacteria; Bacterial Proteins; Nucleotides, Cyclic; Nucleotidyltransferases; Pyrimidines; Second Messenger Systems
PubMed: 30974077
DOI: 10.1016/j.chom.2019.03.016 -
Molecules (Basel, Switzerland) Feb 2020Despite the substantial interest in -glycosyl heterocycles as mimetics of biologically active native glycans, the appearance of -glycopyranosyl derivatives of...
Despite the substantial interest in -glycosyl heterocycles as mimetics of biologically active native glycans, the appearance of -glycopyranosyl derivatives of six-membered heterocycles, both in synthetic and biological contexts, is rather scarce. As part of our ongoing research program aimed at preparing hitherto barely known 2--glycopyranosyl pyrimidines, the goal of the present study was to synthesize new 5-mono- and multiply substituted derivatives of this compound class. Thus, 2--(β-D-glucopyranosyl)-5,6-disubstituted-pyrimidin-4(3)-ones and 4-amino-2--(β-D-glucopyranosyl)-5,6-disubstituted-pyrimidines were prepared by base-mediated cyclocondensations of -perbenzylated and -unprotected -(β-D-glucopyranosyl) formamidine hydrochlorides with methylenemalonic acid derivatives. The 2--(β-D-glucopyranosyl)-5-substituted-pyrimidines were obtained from the same amidine precursors upon treatment with vinamidinium salts. The deprotected derivatives of these pyrimidines were tested as inhibitors of some glycoenzymes. None of them showed inhibitory activity towards glycogen phosphorylase and α- and β-glucosidase enzymes, but some members of the sets exhibited moderate inhibition against bovine liver β-galactosidase.
Topics: Animals; Cattle; Enzyme Inhibitors; Glycogen Phosphorylase; Pyrimidines; alpha-Glucosidases; beta-Galactosidase
PubMed: 32041285
DOI: 10.3390/molecules25030701 -
Molecules (Basel, Switzerland) Oct 2019A small and focused library of steroidal non-fused and fused pyrimidines was prepared from pregnenolone acetate and diosgenin, respectively. The key step was the...
A small and focused library of steroidal non-fused and fused pyrimidines was prepared from pregnenolone acetate and diosgenin, respectively. The key step was the cycloaddition reaction of nitrogen-containing 1,3-binucleophiles with the steroidal α,β-unsaturated ketone. Urea, thiourea and guanidine reacted in a similar manner and afforded the steroidal pyrimidines in good yields. The antiproliferative tests against human tumor cell lines gave GI values in the micromolar range and had no effect on healthy fibroblasts. Additional experiments indicated that the compounds did not act as P-glycoprotein substrates, thus avoiding the rise of drug resistance. The fused steroidal pyrimidinethione was selected as drug lead for further testing due to its strong antiproliferative activities within the low micromolar range.
Topics: Acetates; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Neoplasms; Nitrogen; Pregnenolone; Pyrimidines; Steroids; Structure-Activity Relationship
PubMed: 31614780
DOI: 10.3390/molecules24203676 -
Scientific Reports Jun 2020Uridine phosphorylase (UP) is a key enzyme of pyrimidine salvage pathways that enables the recycling of endogenous or exogenous-supplied pyrimidines and plays an...
Uridine phosphorylase (UP) is a key enzyme of pyrimidine salvage pathways that enables the recycling of endogenous or exogenous-supplied pyrimidines and plays an important intracellular metabolic role. Here, we biochemically and structurally characterized two evolutionarily divergent uridine phosphorylases, PcUP1 and PcUP2 from the oomycete pathogen Phytophthora capsici. Our analysis of other oomycete genomes revealed that both uridine phosphorylases are present in Phytophthora and Pythium genomes, but only UP2 is seen in Saprolegnia spp. which are basal members of the oomycetes. Moreover, uridine phosphorylases are not found in obligate oomycete pathogens such as Hyaloperonospora arabidopsidis and Albugo spp. PcUP1 and PcUP2 are upregulated 300 and 500 fold respectively, within 90 min after infection of pepper leaves. The crystal structures of PcUP1 in ligand-free and in complex with uracil/ribose-1-phosphate, 2'-deoxyuridine/phosphate and thymidine/phosphate were analyzed. Crystal structure of this uridine phosphorylase showed strict conservation of key residues in the binding pocket. Structure analysis of PcUP1 with bound ligands, and site-directed mutagenesis of key residues provide additional support for the "push-pull" model of catalysis. Our study highlights the importance of pyrimidine salvage during the earliest stages of infection.
Topics: Binding Sites; Catalysis; Catalytic Domain; Crystallography, X-Ray; Deoxyuridine; Ligands; Phytophthora; Pyrimidines; Ribosemonophosphates; Thymidine; Uracil; Uridine; Uridine Phosphorylase
PubMed: 32493959
DOI: 10.1038/s41598-020-65935-9 -
Molecules (Basel, Switzerland) Nov 2022Ten new differently substituted 3-benzyl-5-aryl-3,5-dihydro-4-benzo[6,7]chromeno[2,3-]pyrimidin-4,6,11-triones were synthesized by a simple and cost-efficient procedure...
Ten new differently substituted 3-benzyl-5-aryl-3,5-dihydro-4-benzo[6,7]chromeno[2,3-]pyrimidin-4,6,11-triones were synthesized by a simple and cost-efficient procedure in a one-pot, three-component reaction from readily available ethyl 2-amino-4-aryl-5,10-dioxo-5,10-dihydro-4-benzo[]chromene-3-carboxylates, benzylamine and triethyl orthoformate under solvent- and catalyst-free conditions. All the new compounds were screened for their antiproliferative activity against two colorectal-cancer-cell lines. The results showed that the compounds 3-benzyl-5-phenyl-3,5-dihydro-4-benzo[6,7]chromeno[2,3-]pyrimidine-4,6,11-trione () and 3-benzyl-5-(3-hydroxyphenyl)-3,5-dihydro-4-benzo[6,7]chromeno[2,3-]pyrimidine-4,6,11-trione () exhibited the most potent balanced inhibitory activity against human LoVo and HCT-116 cancer cells.
Topics: Humans; Pyrimidines; HCT116 Cells; Benzopyrans; Colorectal Neoplasms
PubMed: 36431976
DOI: 10.3390/molecules27227878 -
ChemMedChem Nov 2021Inhibition of membrane-bound pyrophosphatase (mPPase) with small molecules offer a new approach in the fight against pathogenic protozoan parasites. mPPases are absent...
Inhibition of membrane-bound pyrophosphatase (mPPase) with small molecules offer a new approach in the fight against pathogenic protozoan parasites. mPPases are absent in humans, but essential for many protists as they couple pyrophosphate hydrolysis to the active transport of protons or sodium ions across acidocalcisomal membranes. So far, only few nonphosphorus inhibitors have been reported. Here, we explore the chemical space around previous hits using a combination of screening and synthetic medicinal chemistry, identifying compounds with low micromolar inhibitory activities in the Thermotoga maritima mPPase test system. We furthermore provide early structure-activity relationships around a new scaffold having a pyrazolo[1,5-a]pyrimidine core. The most promising pyrazolo[1,5-a]pyrimidine congener was further investigated and found to inhibit Plasmodium falciparum mPPase in membranes as well as the growth of P. falciparum in an ex vivo survival assay.
Topics: Dose-Response Relationship, Drug; Humans; Molecular Structure; Pyrazoles; Pyrimidines; Pyrophosphatases; Structure-Activity Relationship
PubMed: 34459148
DOI: 10.1002/cmdc.202100392