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Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-activity relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chemistry manipulation of compound 1, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents.

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Alkylation of the monoenolate of N-Boc-l-pyroglutamic acid methyl ester with a variety of benzylic halides and their homologues gave the corresponding anti-C-4-alkylated products as major products. Formation of the N-Boc-iminium ion and Friedel-Crafts intramolecular cationic ring closure afforded a series of fused 1-azacyclodihydroindene derivatives with interesting topologies. Functional diversity was introduced via further manipulation of pendant groups on the original proline motif as well as on the aromatic moiety.

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Aberrant kinase signaling leads to a multitude of disease states. The clinical and commercial success of agents typified by imatinib or dasatinib in the treatment of hematological malignancies has further validated kinase inhibition as a useful clinical strategy. This increased interest in kinases as therapeutic targets is evidenced by the rapidly increasing number of patent applications and peer-reviewed articles. This article discusses recent Patent that describe small molecules targeting the DFG-in active kinase conformation, by the so-called 'Type I½' inhibitor, against a small set of clinically relevant targets such as B-Raf, p38α, Jak2 and EphB4. Preclinical and clinical data are also highlighted for the most promising new molecular entities.

In an effort to design dipeptide structural mimics of protein and peptide reverse-turns, a series of 5,5-, 6,5-, and 7,5-fused 2-oxo-1-azabicycloalkane amino acids has been synthesized. A new and convenient synthetic route utilizing a Eur.