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Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin.
Three pyrazolopyrimidine ATP-competitive mTOR inhibitors are reported, with significant selectivity over phosphatidylinositol 3-kinase (PI3K) isofoms (>100-fold), to highlight mechanistic differentiation between rapalogs and mTOR kinase inhibitors in targeting cancer cell growth and survival and provide support for clinical development of mTORKinase inhibitors as new cancer therapy. Expand
Molecular Mechanism of Hepatitis C Virus Replicon Variants with Reduced Susceptibility to a Benzofuran Inhibitor, HCV-796
The combined virological, biochemical, biophysical, and structural approaches revealed the mechanism of resistance in the variants selected by the potent polymerase inhibitor HCV-796. Expand
Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2.
The results further validate mTOR as a critical driver for tumor growth, establish WYE-132 as a potent and profound anticancer agent, and provide a strong rationale for clinical development of specific mTOR kinase inhibitors as new cancer therapy. Expand
The Development of HKI‐272 and Related Compounds for the Treatment of Cancer
The findings that these irreversible inhibitors retain activity against tumors that have acquired a resistance to the reversible binding inhibitors gefitinib and erlotinib are highlighted. Expand
2,4-Diamino-quinazolines as inhibitors of beta-catenin/Tcf-4 pathway: Potential treatment for colorectal cancer.
Replacement of the biphenyl moiety in compound 1 with the N-phenylpiperidine-4-carboxamide chain resulted in a number of new analogues, which are potent inhibitors of the beta-catenin/Tcf-4 pathway. Expand
Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a
A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea 26 (PKI-587). Expand
Structure-based optimization of protein tyrosine phosphatase 1B inhibitors: from the active site to the second phosphotyrosine binding site.
Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin receptor pathways and thus an attractive therapeutic target for diabetes and obesity. Starting with a highExpand
Discovery of lactoquinomycin and related pyranonaphthoquinones as potent and allosteric inhibitors of AKT/PKB: mechanistic involvement of AKT catalytic activation loop cysteines
Lactoquinomycin is identified as a potent inhibitor of AKT kinases and the role of conserved cysteines in the activation loop (T-loop) is examined to highlight T-loop targeting as a new strategy for the generation of selective AKT inhibitors. Expand
Establishment of In Vitro Susceptibility Testing Methodologies and Comparative Activities of Piperacillin in Combination with the Penem β-Lactamase Inhibitor BLI-489
The novel bicyclic penem inhibitor BLI-489 has demonstrated activity as an inhibitor of class A, C, and D β-lactamases and demonstrated improved activity compared to that of piperacillin-tazobactam against the problematic extended-spectrum β- lactamase- and AmpC-expressing strains. Expand
ATP-competitive inhibitors of the mammalian target of rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidines.
Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models. Expand