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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 structure-activity relationship of a novel subseries of 4-anilinoquinazoline EGFR inhibitors substituted at the C-6 position with carbon-linked side chains has been investigated. This exploration has led to the discovery of novel aminomethyl carboxamides with good biological, pharmacokinetic and physical properties.

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 new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure–activity and structure–property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics.

Aim: First-generation EGFR-TKIs, such as gefitinib, are active in first-line, EGFR-TKI-sensitising-mutant (EGFRm+), advanced NSCLC, but the duration of clinical benefit is limited by acquired tumour resistance. A common resistance mechanism is gain of an additional mutation, T790M, and about 5–15% of patients also develop MET amplification, with or without T790M. The recently developed novel third-generation EGFR-TKI, AZD9291 (a selective EGFR-TKI of EGFRm+ and T790M mutations), overcomes T790M-mediated resistance. Combining EGFR-TKIs with selective molecularly targeted agents has the potential to delay the emergence of EGFR-TKI resistance across lines of therapy. Finally, immunotherapeutics, such as checkpoint inhibitors, have the potential to target cancers orthogonally; thus studies to optimise their use with EGFR-TKIs would be of high value to patients. Methods: In vitro and in vivo preclinical models representing EGFRm+ and T790M NSCLC were used to investigate the potential of combining AZD9291 or gefitinib with immunotherapeutics, and selective small molecule kinase inhibitors, namely selumetinib (AZD6244, ARRY-142886; MEK1/2 inhibitor) and AZD6094 (MET inhibitor). Results: Preclinical models harbouring MET overexpression demonstrated AZD6094 plus EGFR-TKI was well tolerated and effective in reversing MET-driven resistance. In models of acquired resistance mediated by increased MEK dependency, resistance could be delayed in vitro and in vivo by addition of selumetinib. Finally, a genetically engineered mouse model of mutant EGFR NSCLC was used to assess the impact of AZD9291 treatment on T-cell infiltration; results will be presented. Conclusions: These preclinical studies provide a strong rationale for the clinical evaluation of AZD9291 and gefitinib in combination with molecularly targeted agents, such as AZD6094 and selumetinib, to delay and/or overcome acquired resistance to single-agent EGFR-TKI therapy. Rational combinations with immunotherapeutics are also worth further investigation. Disclosure: D. Cross, C. Eberlein, S. Ashton, M. Mellor, P. Smith, M. Frigault and P.J. Jewsbury: Employment and stock ownership: AstraZeneca; C. D'Cruz: Employment: AstraZeneca; R. Stewart: Employment: MedImmune. Stock ownership: AstraZeneca; A. Schuller: Employment: AstraZeneca; W. Pao: Rights to EGFR T790M testing licensed on WP's behalf by MSKCC to MolecularMD. Research funding and travel and consulting funds: AstraZeneca. All other authors have declared no conflicts of interest.

e13599 Background: Simultaneous inhibition of both the PI3K-Akt and RAF/MEK/ERK pathways may yield greater benefits than inhibiting either pathway alone. This phase I study (NCT01021748) examined the safety, pharmacokinetics (PK), pharmacodynamics (PD), maximal tolerated dose (MTD), and preliminary antitumor activity of the combination of a MEKi (selumetinib) and AKTi (MK-2206). Methods: Eligible patients (pts) with advanced solid tumors were treated with MK-2206 either every other day (QOD) or once weekly (QW), in combination with selumetinib administered either once daily (QD) or twice daily (BID). Results: 51 pts with advanced solid tumors (15 colon, 8 NSCLC, 6 ovarian, 5 pancreatic, 3 breast and 14 others) were treated across 9 dose levels. There were 2 confirmed partial response (PR) (1 NSCLC, ongoing > 52 wks; 1 ovarian, on treatment for 47 weeks; both KRAS mutation positive), 1 unconfirmed PR (pancreatic, on treatment 20 wks), and 24 pts with stable disease (ranged from 6 to 47 wks). Preliminary assessment of PK data suggested no apparent drug-drug interactions with unaltered PK profiles of each drug when administered in combination. Conclusions: In combination the maximum tolerated doses of MK-2206 and selumetinib are 135 mg QW and 100 mg QD, respectively. This combination of investigational agents demonstrated preliminary antitumor activity in pts with advanced cancer. [Table: see text]

BACKGROUND Emphysema associated with alpha 1-antitryp sin deficiency can impose serious impairment. OBJECTIVE To gather information about the impact of severe alpha 1-antitrypsin deficiency. METHODS Mail survey, descriptive statistics. RESULTS We sent a survey to 1730 subscribers to a national newsletter, 850 of whom had previously stated they had alpha 1-antitrypsin deficiency. A total of 414 questionnaires were returned; 398 respondents said they had alpha 1-antitrypsin deficiency, and 300 said they had the PiZZ phenotype. Sixty-six respondents who said they had the disease did not know their phenotype. Among the 304 respondents with severe deficiency, the mean age at the time symptoms first appeared was 35.0 years, but the mean age when the disease was diagnosed was 41.3 years. Overall, 75.3% of respondents with severe deficiency reported at least one adverse effect: 44-4% retired early, and 19.1% changed to a physically easier job. The duration of diagnostic delay correlated with the degree of adverse psychosocial effects. CONCLUSIONS Alpha 1-antitrypsin deficiency frequently escapes diagnosis despite many medical encounters. Affected individuals are often unaware of basic details of their disease. Many patients report adverse psychosocial effects. Delay in diagnosing this disease is associated with adverse psychosocial effects.

T may make this review a little more meaningful if I present my credentials-not because the story of my life has any great relevance, but because it seems to me that a review is only "placed" if something is known about the background of the reviewer. How I judge what I saw at Ashland and San Add >& Diego this summer inevitably depends on what I already know about Shakespearian production, and that in turn depends, mainly, on what I have seen and studied in other theaters elsewhere. My "terms of reference" then are these: I write as a spectator, a member of the audience, rather than as someone who has acted and directed Shakespeare. Every summer from i95i to i965 I saw the productions of one or other of the two major Shakespeare Festivals-those in Stratford-on-Avon and in Stratford, Ontario. With the help of a few side trips to London, Edinburgh, Toronto, Stratford, Connecticut, Minneapolis, the Birmingham Rep., and the Nottingham Playhouse, I have managed to see professional productions of 35 of the 37 plays. Most of these productions have been mounted with all the lavishness that has come to be associated with well-established Shakespeare companies under distinguished leadership. About half the productions I have seen have been on proscenium stages, and about half on thrust stages. I like going to the theater, and I especially like going to see Shakespeare. While not uncritical, I believe that I have enjoyed almost every production I have ever seen, and although only ten or a dozen have seemed to me to be truly worthy of their author, I take this to be a high average and I do not feel I have any cause for complaint. When I came to live on the West Coast last year I was glad to think that even though this meant leaving the three Stratfords far behind it did not mean that I should have to have a summer without Shakespeare. I had read about Ashland and the San Diego Old Globe, and I was keen to visit them and to see where they stood in my personal assessment of the Shakespeare industryto compare them not only with each other but with the other companies I had seen. It has proved to be a very enlightening and enjoyable experience; writing about it all, however, is a horse of a different color. I find that I am not sure what standards to apply. Shall I compare these seasons with those in Warwickshire or Ontario? This is patently unfair, since shorter seasons, smaller seating capacities, absence of subsidies, and the inevitable lack of resources that come from these, make ,the comparison meaningless. Comparison, on the other hand, with amateur productions I have seen in

E are told that W. S. Gilbert, incensed by criticism of both the title and the production of his new piece, Ruddigore, threatened to change its name to "Kensington Gore, or Not So Good As The Mikado". To my ear there is much more bitterness revealed in the second half of the new title than in the first; indeed I suspect that few comments are more likely to touch theater people on the raw than ones that suggest that there's been a falling off. Yet every so often such comments are the ones that come most readily to mind and, especially in a review that is a part of an annual survey of Shakespeare companies around the world, they have a place. To say that the I970 season at Stratford, Connecticut was not as good as the i969 one is, in part, to add another compliment to the ones already paid to last year's. The i969 season both marked a turning point and set a standard. The significant thing about I970 was not so much that it failed to come up to the previous year's standard as that it succeeded in maintaining the new outlook. It was still clearly headed in the right direction. And that fact alone made a visit there well worth while. Michael Kahn, the Artistic Director, continues to put his money where it counts most-into bringing good actors who know how to speak Shakespeare. Whatever criticisms may be made about this season are criticisms of details, not of fundamentals. Whatever disappointment afflicted one had to do with means rather than ends. All of which indicates that basically one is dealing with a company that deserves to be taken seriously as a member of the big leagues. If there is one thing that is fundamentally wrong it is something that Mr. Kahn has no real control over-the design of the theater. Again and again the drawbacks of that stage were apparent; in fact the thought crosses one's mind that whoever designed it must have hated actors, wanting to make them look tiny and insignificant in comparison with the structure, wanting to make exits and entrances absurdly difficult and unnatural, and at the same time forcing scene designers to spend valuable money on filling useless space or on creaky distracting furniture-on-wheels. If the Trustees of the Festival really want to show how much they value Michael Kahn's services they will surely concentrate some effort on providing him with a better instrument on which to perform. That he deserves such consideration is clear from his activities this season. In strong contrast with his bold and unorthodox approach to Henvy V in i969, his productions this season (he was responsible for both the Shakespeare plays in the repertoire) were "straight" and straightforward; and, as we all know, such productions are much harder to realize. Small wonder, then, if some of the inconsistencies showed through and if some of the inadequacies