Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships.

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.

IP issues facing researchers by Gino D'Oca.

Patents are clearly one of the main drivers of innovation in pharmaceutical and medical R&D. It is increasingly important for researchers at the sharp end to be familiar with the ins and outs of the patenting process. In this feature a panel of experts from academia and industry discuss their experiences of analyzing the patent landscape and preparing applications. Interview conducted by Gino D'Oca, Managing Commissioning Editor.

Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors.

The synthesis and SAR of a series of novel pyrazolo-quinazolines as potent and selective MPS1 inhibitors are reported. We describe the optimization of the initial hit, identified by screening the internal library collection, into an orally available, potent and selective MPS1 inhibitor.

Targeting the DFG-in kinase conformation: a new trend emerging from a patent analysis.

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.

Structure-based optimization of potent PDK1 inhibitors.

In this Letter is described the structure-based design of potent dihydro-pyrazoloquinazolines as PDK1 inhibitors. Starting from low potency HTS hits with the aid of X-ray crystallography and modeling, a medicinal chemistry activity was carried out to improve potency versus PDK1 and selectivity versus CDK2 protein kinase.

Synthesis of functionally diverse and conformationally constrained polycyclic analogues of proline and prolinol.

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.

Conformationally stable and constrained macrocarbocyclic pseudopeptide mimics of beta-hairpin structures.

Subjecting a D-Pro-L-Pro template harboring N- and C-terminal omega-alkenyl amino acids to a ring-closure metathesis reaction afforded the corresponding macrocyclic alkenes. A cis-alkene analogue crystallized with one molecule each of water and chloroform, which were retained even after heating at 100 degrees C. By using the reduced macrocyclic product as a template, the metathesis could be repeated twice on newly installed omega-alkenyl amino acids to give three-tiered macrocarbocyclic pseudopeptides as mixtures of conformers. NMR studies revealed the high conformational stability of these motifs.