Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.

The after-action review (AAR) is a discussion technique some high-reliability organizations employ to encourage learning via collective retrospection. AARs are an effective communication tool for promoting reliability if they are held regularly. One way to encourage frequent AARs is to increase participants’ satisfaction with these meetings. This study examined the impact of post-incident, pre-discussion ambiguity and freedom of dissent on participant satisfaction with AARs. Firefighters (N = 119) completed a survey on their most recent AAR. As predicted, the level of post-incident, pre-discussion ambiguity was negatively related to AAR satisfaction. Freedom of dissent, however, attenuated the negative influence of ambiguity on AAR satisfaction.

In some patients who do not achieve an SVR, drug-resistant variants have been reported.A better understanding of the long-term persistence of these variants is needed.The aim of this study was to assess the prevalence of variants in patients both before treatment with telaprevir and at long term follow-up by using sensitive ultra-deep pyrosequencing (UDPS).Methods: Fourteen patients were recruited from 2 phase 1 clinical studies (VX101 and 103) of telaprevir.In these trials patients received either telaprevir monotherapy for 14 days or combination therapy with Peg-IFN.Previously well-described resistant variants at NS3 protease positions V36, T54, R155 and A156 were assessed at baseline and after a follow-up of 4±1.2 years by UDPS on the Roche 454 GS FLX platform.Resistant variants were tabulated at each time point and compared statistically between time points at each position using Fisher Exact tests, with Type I error controlled with the Bonferroni correction.Results: Median number of sequence reads per position ranged from 4677-13326.Prevalence of variants associated with resistance to telaprevir at baseline was found to be very low.The highest baseline prevalence was observed in a patient carrying a T54A variant (0.54%).No resistant variants were detected in 9 of 14 patients at baseline as compared to 8 of 14 at long-term followup.In 13 of 14 patients, there was no indication of significant enrichment of resistant variants at the long-term follow-up time point relative to baseline, despite the presence of resistant variants in the clinical trial in all patients.The remaining patient had both V36M and T54S significantly enriched at long-term follow-up (4.5% and 0.35%, respectively) relative to baseline, where neither variant was observed. Conclusion:In patients treated for 14 days with telaprevir monotherapy or in combination with Peg-IFN, highly sensitive sequencing methods indicated that resistant variants do not typically persist long-term.

The discovery of 5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10 microM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed.

5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; IC(50) (1a)<25nM, EC(50) (1b)=16nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F=24%).

A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.

A 4-step synthesis of an optically active synthetic intermediate [(1R,2S)-2-(4′-fluorobenzylamino)cyclopentanecarboxylic acid ethyl ester complex with (S)-(+)-mandelic acid; compound 12, >99% de] required for the preparation of a promising HCV NS5B polymerase inhibitor is reported. This process utilizes mandelic acid as a resolving agent, which can be recovered in good yield by a simple extraction. An optimized version of the chemistry described avoids the use of chromatographic purifications making it suitable for large-scale applications. In addition, the straightforward conversion of compound 12 to enantiomerically pure (1R,2S)-2-aminocyclopentanecarboxylic acid ethyl ester and the corresponding Boc and Cbz derivatives is reported. The preparation of the enantiomer of 12 (compound 15) in enantiomerically pure form and the conversion of this entity to (1S,2R)-2-aminocyclopentanecarboxylic acid ethyl ester and the corresponding Boc and Cbz derivatives is also described.

5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The structure–activity relationship (SAR) associated with variation of the pyridazinone 2- and 6-substituents is discussed. The synthesis and metabolic stability of this new class of compounds are also described.

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Translation inhibitors of the 3,5-diamino-piperidine series act as aminoglycoside mimetics that inhibit bacterial growth. Here we show antibacterial SAR in the presence and absence of serum with a particular focus toward Pseudomonas aeruginosa.

5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as potent inhibitors of genotype 1 HCV NS5B polymerase focusing on the optimization of their drug metabolism and pharmacokinetics (DMPK) profiles. This investigation led to the discovery of potent inhibitors with improved DMPK properties.

A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50) of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.

The synthesis of a novel class of 6-amino-5-hydroxypyridazin-3(2H)-ones (3-oxo-2,3-dihydropyridazines) is described. These compounds also contain an ethoxycarbonyl moiety at the 4-position of the pyridazinone ring. They are prepared in good to moderate yields (30-72%) by the condensation of disubstituted amines with (alkythydrazono)- or (arylhydrazono)(chloro)acetates followed by subsequent acylation with ethyl malonyl chloride and Dieckmann cyclization. An initial assessment of the scope and limitations of the new methodology is described along with the novel synthesis of several (alkylhydrazono)(chloro)acetate substrates utilized in the pyridazinone preparations.