Collaborative Virtual Screening Identifies a 2-Aryl-4-aminoquinazoline Series with Efficacy in an In Vivo Model of Trypanosoma cruzi Infection

Probing multiple proprietary pharmaceutical libraries in parallel via virtual screening allowed rapid expansion of the structure-activity relationship (SAR) around hit compounds with moderate efficacy against Trypanosoma cruzi, the causative agent of Chagas Disease. A potency-improving scaffold hop, followed by elaboration of the SAR via design guided by the output of the phenotypic virtual screening efforts, identified two promising hit compounds 54 and 85, which were profiled further in pharmacokinetic studies and in an in vivo model of T. cruzi infection. Compound 85 demonstrated clear reduction of parasitemia in the in vivo setting, confirming the interest in this series of 2-(pyridin-2-yl)quinazolines as potential anti-trypanosome treatments

Studies into the total synthesis of batrachotoxin

A stereospecific synthesis of the AB rings of batrachotoxin has been developed. Formation of the silyl enol ether of a 1-keto hexahydroindene was followed by dibromocarbene insertion and `in-situ' ring expansion. Stereoselective attack of the resulting α bromo ketone with lithium acetylide afforded the desired fragment of batrachotoxin. An alternative AB ring synthesis has also been examined, involving a novel carbene mediated ring expansion as its key step. Construction of the C^3-C^9 hemiketal bridge has been considered in some detail. Molecular modelling being used in an attempt to understand the principles governing formation of this linkage. Finally synthetic methodology has also been developed towards the CD rings. 2-Ethynyl-3-methoxycyclopent-2-enone was prepared via a palladium and copper catalysed coupling of 3-ethoxy-2-iodocyclopent-2-enone with (trimethylsilyl)acetylene.</p

Creativity, innovation and lean sigma: a controversial combination? Drug Discov

The application of lean sigma is gaining momentum in drug discovery and development but it remains controversial because of perceptions that process improvement will suppress much-needed creativity and innovation. We review the conditions required to support creativity and innovation and the principles and benefits of lean sigma in a drug discovery environment. We conclude that it is desirable to create a unified climate that encourages and enables both innovation and continuous improvement and that this is possible if three key tensions are handled carefully and with due respect to the needs of research. These three potential traps occur in the interpretation of standardization, the role of variation and the choice of how to use liberated capacity

A genetically selected cyclic peptide inhibitor of BCL6 homodimerization

We report an inhibitor of the homodimeric protein-protein interaction of the BCL6 oncoprotein, identified from a genetically encoded SICLOPPS library of 3.2 million cyclic hexapeptides in combination with a bacterial reverse two-hybrid system. This cyclic peptide is shown to bind the BTB domain of BCL6, disrupts its homodimerization, and subsequent binding of the SMRT2 corepressor peptide

One-pot four-component reaction for the generation of pyrazoles and pyrimidines

The palladium-catalysed four-component coupling of a halide, terminal alkyne, molybdenum hexacarbonyl and either a hydrazine or amidine has been shown to be an efficient method for the construction of highly substituted pyrazoles and pyrimidines, respectively, in a one-pot proces

Inhibition of low-density lipoprotein receptor degradation with a cyclic peptide that disrupts the homodimerization of IDOL E3 ubiquitin ligase

Cellular uptake of circulating cholesterol occurs via the low density lipoprotein receptor (LDLR). The E3 ubiquitin ligase IDOL is a mediator of LDLR degradation, with IDOL homodimerization thought to be required for its activity. To probe the possibility of modulating LDLR levels with an inhibitor of IDOL homodimerization, we screened a SICLOPPS library of 3.2 million cyclic peptides for compounds that disrupt this protein-protein interaction. We identified cyclo-CFFLYT as the lead inhibitor, and improved its activity through the incorporation of non-natural amino acids. The activity of the optimized cyclic peptide was assessed in hepatic cells, with a dose-dependent increase in LDLR levels observed in the presence of our IDOL homodimerization inhibitor

Dataset for Inhibition of low-density lipoprotein receptor degradation with a cyclic peptide that disrupts the homodimerization of IDOL E3 ubiquitin ligase

Raw data supporting: Leitch, E. et al (2018). Inhibition of low-density lipoprotein receptor degradation with a cyclic peptide that disrupts the homodimerization of IDOL E3 ubiquitin ligase. Chemical Science. </span