The Pim protein kinases are frequently overexpressed in prostate cancer and certain forms of leukemia lymphoma. 5-(3-Trifluoromethylbenzylidene)thiazolidine-2,4-dione (4a) was identified by screening to be a Pim-1 inhibitor found attenuate the autophosphorylation tagged intact cells. Although 4a is competitive with respect ATP, screen approximately 50 diverse demonstrated that it has high selectivity for kinases. Computational docking provided model lead optimization, series substituted...

The serine/threonine Pim kinases are overexpressed in solid cancers and hematologic malignancies promote cell growth survival. Here, we find that a novel kinase inhibitor, SMI-4a, or Pim-1 siRNA blocked the rapamycin-sensitive mammalian target of rapamycin (mTORC1) activity by stimulating phosphorylation thus activating mTORC1 negative regulator AMP-dependent protein (AMPK). Mouse embryonic fibroblasts (MEFs) deficient for all three [triple knockout (TKO) MEFs] demonstrated activated AMPK...

Abstract The covalent attachment of palmitate to specific proteins by the action palmitoyl acyltransferases (PAT) plays critical roles in biological activities several oncoproteins. Two PAT are expressed human cells: type 1 PATs that modify farnesyl-dependent palmitoylation motif found H- and N-Ras, 2 myristoyl-dependent Src family tyrosine kinases. We have previously shown HIP14 causes cellular transformation. In current study, we show mRNA encoding is up-regulated a number types tumors. To...

Abstract The Pim protein kinases play important roles in cancer development and progression, including prostate tumors hematologic malignancies. To investigate the potential role of these enzymes as anticancer drug targets, we have synthesized novel benzylidene-thiazolidine-2,4-diones that function potent kinase inhibitors. With IC50 values nanomolar range, compounds block ability to phosphorylate peptides proteins vitro and, when added DU145 cells overexpressing Pim, inhibit this enzyme a...

Abstract The ceramide/sphingosine-1-phosphate (S1P) rheostat has been hypothesized to play a critical role in regulating tumor cell fate, with elevated levels of ceramide inducing death and S1P leading survival proliferation. Ceramidases are key enzymes that control this by hydrolyzing produce sphingosine may also confer resistance drugs radiation. Therefore, ceramidase inhibitors have excellent potential for development as new anticancer drugs. In study, we identify novel inhibitor...

Dendroamide A (1) was isolated from a blue-green alga on the basis of its ability to reverse drug resistance in tumor cells that overexpress either transport proteins, P-glycoprotein or MRP1. Because this activity, methods for synthesis analogues oxazole- and thiazole-containing cyclic peptide have been developed, total 1 has completed. Highlights synthetic strategy are as follows: dicyclohexylcarbodiimide coupling d-Ala l-Thr, followed by reaction with Burgess reagent DBU-assisted oxidation...

In a search for improved multiple drug resistance (MDR) modulators, we identified novel series of substituted pyrroloquinolines that selectively inhibits the function P-glycoprotein (Pgp) without modulating multidrug resistance-related protein 1 (MRP1). These compounds were evaluated their toxicity toward drug-sensitive tumor cells (i.e. MCF-7, T24) and ability to antagonize Pgp-mediated drug-resistant NCI/ADR) MRP1-mediated resistant MCF-7/VP). Cytotoxicity accumulation assays demonstrated...

Many important signaling proteins require the posttranslational addition of fatty acid chains for their proper subcellular localization and function. One such modification is palmitoyl moieties by enzymes known as acyltransferases (PATs). Substrates PATs include C-terminally farnesylated proteins, H- N-Ras, well N-terminally myristoylated many Src-related tyrosine kinases. The molecular biochemical characterization has been hindered difficulties in developing effective methods analysis PAT...

Objective Exemestane (EXE) is a potent third-generation aromatase inhibitor used as endocrine therapy in breast cancer treatment and prevention. Characterization of its metabolic pathway incomplete, with ambiguity existing the identity enzymes driving production key metabolite, 17β-dihydroexemestane (17β-DHE). The impact genetic variation on EXE metabolism also unknown. This study aims to describe cytosolic reductase involvement hepatic assess functional polymorphisms metabolite production....

The covalent attachment of palmitate to proteins commonly occurs on cysteine residues near either N-myristoylated glycine or C-terminal farnesylated residues. It therefore seems likely that multiple palmitoyl-acyl transferase (PAT) activities exist recognize and modify these distinct palmitoylation motifs. To evaluate this possibility, two synthetic peptides representing motifs, termed MyrGCK(NBD) FarnCNRas(NBD), were used characterize PAT activity under a variety conditions. human tumour...

<i>N</i>-Myristoyltransferase (NMT) is an emerging therapeutic target that catalyzes the attachment of myristate to N terminus acceptor protein. We have developed a medium-throughput assay for screening potential small molecule inhibitors human NMT-1 consisting recombinant enzyme, biotinylated peptide substrate, and [³H]myristoyl-CoA. Approximately 16,000 diverse compounds been evaluated, significant inhibition NMT was found with 0.8% compounds. From these hits, we identified...

Cigarette smoking causes nearly one in every five deaths the United States. The development of a specific inhibitor cytochrome P450 2A6 (CYP2A6), major nicotine-metabolizing enzyme humans, which could be prescribed for cessation cigarette smoking, has been undertaken. To further refine structure activity relationship CYP2A6, previously synthesized 3-alkynyl and 3-heteroaromatic substituted pyridine methanamines were used as lead compounds. Isosteric replacement appendage all available...

Abstract Exemestane ( EXE ) is an endocrine therapy commonly used by postmenopausal women with hormone‐responsive breast cancer due to its potency in inhibiting aromatase‐catalyzed estrogen synthesis. Preliminary vitro studies sought identify phase I metabolites and hepatic cytochrome P450s CYP 450s) that participate biotransformation. Phase were identified incubating HEK 293‐overexpressed 450s. 450s 1A2, 2C8, 2C9, 2C19, 2D6, 3A4, 3A5 produce 17 β ‐dihydroexemestane (17 ‐ DHE ), active major...

Exemestane (EXE) is an aromatase inhibitor used for the prevention and treatment of estrogen receptor-positive breast cancer. Although known major metabolic pathway EXE reduction to form active 17β-dihydro-EXE (17β-DHE) subsequent glucuronidation 17β-hydroxy-EXE-17-O-β-D-glucuronide (17β-DHE-Gluc), previous studies have suggested that other metabolites exist exemestane. In present study, a liquid chromatography-mass spectrometry (LC-MS) approach was acquire accurate mass data in MSE mode,...

Abstract Exemestane ( EXE ) treats estrogen receptor positive ER +) breast cancer in postmenopausal women by inhibiting the estrogen‐synthesizing cytochrome P450 CYP 19A1. Variability severity and incidence of side effects as well overall drug efficacy may be partially explained genetic factors, including nonsynonymous variation 19A1, also known aromatase. The present study identified phase I metabolites human liver microsomes HLM investigated mechanisms that alter extent systemic...

ADVERTISEMENT RETURN TO ISSUEPREVNoteNEXTEfficient Synthesis of a Fluorescent Farnesylated Ras PeptideZuping Xia and Charles D. SmithView Author Information Department Pharmacology, Pennsylvania State University, Hershey, 17033 [email protected]Cite this: J. Org. Chem. 2001, 66, 15, 5241–5244Publication Date (Web):July 4, 2001Publication History Received17 January 2001Published online4 July inissue 1...

Exemestane (EXE) is a hormonal therapy used to treat estrogen receptor–positive breast cancer by inhibiting the final step of biosynthesis catalyzed enzyme aromatase. Cysteine conjugates EXE and its active metabolite 17β-dihydro-EXE (DHE) are major metabolites found in both urine plasma patients taking EXE. The initial cysteine conjugate formation glutathione conjugation <i>S</i>-transferase (GST) family enzymes. goal present study was identify cytosolic hepatic GSTs GST-mediated metabolism...

3’-O-Retinoyl-5-fluoro-2’-deoxyuridine (RFUdR) is a putative dual-acting, mutually-masking (DAMM) prodrug for the treatment of cancer. As part proof principle DAMM concept, concentrations RFUdR and its post-hydrolysis active metabolites, 5-fluoro-2’-deoxyuridine (FUdR) all-trans-retinoic acid (RA), were determined in plasma selected tissues following either bolus intravenous (i.v.; 12.5 μmol/kg) or oral (p.o.; 13.7 doses to mice bearing EMT6 murine mammary tumors. The primary metabolites...

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