Intestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol uptake, but how cholesterol moves downstream of NPC1L1 is unknown. We show that Aster-B and Aster-C are critical for nonvesicular cholesterol movement in enterocytes.
View Article and Find Full Text PDFWall teichoic acid (WTA) polymers are covalently affixed to the Gram-positive bacterial cell wall and have important functions in cell elongation, cell morphology, biofilm formation, and β-lactam antibiotic resistance. The first committed step in WTA biosynthesis is catalyzed by the TagA glycosyltransferase (also called TarA), a peripheral membrane protein that produces the conserved linkage unit, which joins WTA to the cell wall peptidoglycan. TagA contains a conserved GT26 core domain followed by a C-terminal polypeptide tail that is important for catalysis and membrane binding.
View Article and Find Full Text PDFThe 4-anilino-6,7-ethylenedioxy-5-fluoroquinazoline scaffold is presented as a novel model system for the characterization of the weak NH⋅⋅⋅F hydrogen bonding (HB) interaction. In this scaffold, the aniline NH proton is forced into close proximity with the nearby fluorine (d ∼2.0 Å, ∠∼138°), and a through-space interaction is observed by NMR spectroscopy with couplings ( J ) of 19±1 Hz.
View Article and Find Full Text PDFThe androgen receptor (AR) is critical in the progression of prostate cancer (PCa). Small molecule antagonists that bind to the ligand binding domain (LBD) of the AR have been successful in treating PCa. However, the structural basis by which the AR antagonists manifest their therapeutic efficacy remains unclear, due to the lack of detailed structural information of the AR bound to the antagonists.
View Article and Find Full Text PDFWe previously reported several vignettes on types and classes of drugs able to mitigate acute and, in at least one case, late radiation syndromes in mice. Most of these had emerged from high throughput screening (HTS) of bioactive and chemical drug libraries using ionizing radiation-induced lymphocytic apoptosis as a readout. Here we report the full analysis of the HTS screen of libraries with 85,000 small molecule chemicals that identified 220 "hits.
View Article and Find Full Text PDFHerein, we report the synthesis and evaluation of novel analogues of UK-5099 both and for the development of mitochondrial pyruvate carrier (MPC) inhibitors to treat hair loss. A comprehensive understanding of the structure-activity relationship was obtained by varying four positions of the hit compound, namely, the alkyl group on the N1 position, substituents on the indole core, various aromatic and heteroaromatic core structures, and various Michael acceptors. The major discovery was that the inhibitors with a 3,5-bis(trifluoromethyl)benzyl group at the N1 position were shown to have much better activity than (UK-5099) to increase cellular lactate production.
View Article and Find Full Text PDFA potent class of isoquinoline-based α-N-heterocyclic carboxaldehyde thiosemicarbazone (HCT) compounds has been rediscovered; based upon this scaffold, three series of antiproliferative agents were synthesized through iterative rounds of methylation and fluorination modifications, with anticancer activities being potentiated by physiologically relevant levels of copper. The lead compound, , was highly potent against a panel of pancreatic, small cell lung carcinoma, prostate cancer, and leukemia models, with IC values in the low-to-mid nanomolar range. Density functional theory (DFT) calculations showed that fluorination at the 6-position of was beneficial for ligand-copper complex formation, stability, and ease of metal-center reduction.
View Article and Find Full Text PDFThe Aster proteins (encoded by the genes) contain a ligand-binding fold structurally similar to a START domain and mediate nonvesicular plasma membrane (PM) to endoplasmic reticulum (ER) cholesterol transport. In an effort to develop small molecule modulators of Asters, we identified 20α-hydroxycholesterol (HC) and U18666A as lead compounds. Unfortunately, both 20α-HC and U18666A target other sterol homeostatic proteins, limiting their utility.
View Article and Find Full Text PDFThe epidermal growth factor receptor (EGFR) is genetically altered in nearly 60% of glioblastoma tumors; however, tyrosine kinase inhibitors (TKIs) against EGFR have failed to show efficacy for patients with these lethal brain tumors. This failure is attributed to the inability of clinically tested EGFR TKIs to cross the blood-brain barrier (BBB) and achieve adequate pharmacological levels to inhibit various oncogenic forms of EGFR that drive glioblastoma. Through SAR analysis, we developed compound (JCN037) from an anilinoquinazoline scaffold by ring fusion of the 6,7-dialkoxy groups to reduce the number of rotatable bonds and polar surface area and by introduction of an -fluorine and -bromine on the aniline ring for improved potency and BBB penetration.
View Article and Find Full Text PDFSortase enzymes are attractive antivirulence drug targets that attach virulence factors to the surface of Staphylococcus aureus and other medically significant bacterial pathogens. Prior efforts to discover a useful sortase inhibitor have relied upon an in vitro activity assay in which the enzyme is removed from its native site on the bacterial surface and truncated to improve solubility. To discover inhibitors that are effective in inactivating sortases in vivo, we developed and implemented a novel cell-based screen using Actinomyces oris, a key colonizer in the development of oral biofilms.
View Article and Find Full Text PDFBackground: Deoxycytidine kinase (dCK) is an essential enzyme for production of nucleotides via the salvage pathway; DI-87 is a novel dCK inhibitor in preclinical development for use in anticancer therapy. The current study utilizes PET imaging to evaluate PK-PD relationships and to determine optimal dosing of the drug.
Methods: NSG mice bearing CEM tumors had plasma and tumor PK assessed using mass spectrometry following oral administration of DI-87.
Biosynthesis of the pyrimidine nucleotide uridine monophosphate (UMP) is essential for cell proliferation and is achieved by the activity of convergent de novo and salvage metabolic pathways. Here we report the development and application of a cell-based metabolic modifier screening platform that leverages the redundancy in pyrimidine metabolism for the discovery of selective UMP biosynthesis modulators. In evaluating a library of protein kinase inhibitors, we identified multiple compounds that possess nucleotide metabolism modifying activity.
View Article and Find Full Text PDFDetermination of the amino acid phenylalanine is important for lifelong disease management in patients with phenylketonuria, a genetic disorder in which phenylalanine accumulates and persists at levels that alter brain development and cause permanent neurological damage and cognitive dysfunction. Recent approaches for treating phenylketonuria focus on injectable medications that efficiently break down phenylalanine but sometimes result in detrimentally low phenylalanine levels. We have identified new DNA aptamers for phenylalanine in two formats, initially as fluorescent sensors and then, incorporated with field-effect transistors (FETs).
View Article and Find Full Text PDFReceptor type protein tyrosine phosphatase-sigma (PTPσ) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTPσ is also expressed by hematopoietic stem cells (HSCs). Here, we describe small molecule inhibitors of PTPσ that promote HSC regeneration in vivo.
View Article and Find Full Text PDFPrior work indicates DEPTOR expression in multiple myeloma cells could be a therapeutic target. DEPTOR binds to mTOR via its PDZ domain and inhibits mTOR kinase activity. We previously identified a drug, which prevented mTOR-DEPTOR binding (NSC126405) and induced multiple myeloma cytotoxicity.
View Article and Find Full Text PDFBreast cancers (BCs) with expression of estrogen receptor-alpha (ERα) occur in more than 70% of newly-diagnosed patients in the U.S. Endocrine therapy with antiestrogens or aromatase inhibitors is an important intervention for BCs that express ERα, and it remains one of the most effective targeted treatment strategies.
View Article and Find Full Text PDFThe Mannich reaction has been used for decades to prepare many pharmaceutically important molecules. Here, using a "double-Mannich-β-elimination" synthetic sequence, we report the synthesis and the characterization details of a novel class of β-amino diaryldienones with prominent antiprostate cancer activity. Through these studies, we correct an erroneous structure in the current literature, present a discussion of the stereochemical outcome of a new reaction, and probe the mechanism(s) of byproduct formation through isotopic studies.
View Article and Find Full Text PDFProstate cancer (PCa) is the second most common cause of cancer-related mortality in men in the United States. The androgen receptor (AR) and the physiological pathways it regulates are central to the initiation and progression of PCa. As a member of the nuclear steroid receptor family, it is a transcription factor with three distinct functional domains (ligand-binding domain [LBD], DNA-binding domain [DBD], and transactivation domain [TAD]) in its structure.
View Article and Find Full Text PDFWe describe here the results from the testing of a small molecule first-in-class apolipoprotein E4 (ApoE4)-targeted sirtuin1 (SirT1) enhancer, A03, that increases the levels of the neuroprotective enzyme SirT1 while not affecting levels of neurotoxic sirtuin 2 (SirT2) in vitro in ApoE4-transfected cells. A03 was identified by high-throughput screening (HTS) and found to be orally bioavailable and brain penetrant. In vivo, A03 treatment increased SirT1 levels in the hippocampus of 5XFAD-ApoE4 (E4FAD) Alzheimer's disease (AD) model mice and elicited cognitive improvement while inducing no observed toxicity.
View Article and Find Full Text PDFThe aquaculture industry is growing rapidly to meet the needs for global protein consumption. Viral diseases in aquaculture are quite challenging due to lack of treatment options as well as limited injection-delivery vaccines, which are costly. Thus, water-immersion antiviral treatments are highly desirable.
View Article and Find Full Text PDFA series of novel pyrazolopyridine compounds have been designed and prepared by a general synthetic route. Their activities against the replication of poliovirus-1, EV-A71, and CV-B3 enteroviruses were evaluated. The comprehensive understanding of the structure-activity relationship was obtained by utilizing the variation of four positions, namely, N1, C6, C4, and linker unit.
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