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.

No abstract

The Aurora kinases have been the subject of considerable interest as targets for the development of new anticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronounced antiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both Aurora A and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-fold selectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compounds have been designed for parenteral administration and achieve high levels of solubility by virtue of their ability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively converted to the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic properties and safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.

Abstract:Weather events have the potential to greatly impact business operations and profitability, especially in outdoor-oriented economic sectors such as Tourism, Recreation, and Leisure (TRL). Although a substantive body of work focuses on the macroscale impacts of climate change, less is known about how daily weather events influence attendance decisions, particularly relating to the physiological thermal comfort levels of each visitor. To address this imbalance, this paper focuses on ambient thermal environments and visitor behavior at the Phoenix and Atlanta zoos. Daily visitor attendances at each zoo from September 2001 to June 2011, were paired with the Physiologically Equivalent Temperature (PET) to help measure the thermal conditions most likely experienced by zoo visitors. PET was calculated using hourly atmospheric variables of temperature, humidity, wind speed, and cloud cover from 7 a.m. to 7 p.m. at each zoological park location and then classified based on thermal comfort categories established by the American Society of Heating and Air Conditioning Engineers (ASHRAE). The major findings suggested that in both Phoenix and Atlanta, optimal thermal regimes for peak attendance occurred within "slightly warm" and "warm" PET-based thermal categories. Additionally, visitors seemed to be averse to the most commonly occurring thermal extreme since visitors appeared to avoid the zoo on excessively hot days in Phoenix and excessively cold days in Atlanta. Finally, changes in the daily weather impacted visitor attendance as both zoos experienced peak attendance on days with dynamic changes in the thermal regimes and depressed attendances on days with stagnant thermal regimes. Building a better understanding of how weather events impact visitor demand can help improve our assessments of the potential impacts future climate change may have on tourism.

Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88 diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.