Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.

A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.

The piperidine ring is the commonest heterocyclic subunit of natural products, and is a key part of numerous drugs. This article identifies the best asymmetric routes to the piperidine ring system, emphasising methods that are efficient, reliable and flexible. The cover picture shows the plant poison hemlock, which is a source of many piperidine alkaloids such as coniine.

Abstract.A fast neutron (FN)-mutagenised population was generated in Pisum sativum L. (pea) to enable the identification and isolation of genes underlying traits and processes. Studies of several phenotypic traits have clearly demonstrated the utility of the resource by associating gene deletions with phenotype followed by functional tests exploiting additional mutant sources, from both induced and natural variant germplasm. For forward genetic screens, next generation sequencing methodologies provide an opportunity for identifying genes associated with deletions rapidly and systematically. The application of rapid reverse genetic screens of the fast neutron mutant pea population supports conclusions on the frequency of deletions based on phenotype alone. These studies also suggest that large deletions affecting one or more loci can be non-deleterious to the pea genome, yielding mutants that could not be obtained by other means. Deletion mutants affecting genes associated with seed metabolism and storage are providing unique opportunities to identify the products of complex and related gene families, and to study the downstream consequences of such deletions.

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