A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The benefits of farnesoid X receptor (FXR) agonists in patients with non-alcoholic steatohepatitis (NASH) have been validated, although improvements in efficacy and/or tolerability remain elusive. Herein, we aimed to assess the performance of a structurally optimized FXR agonist in patients with NASH. METHODS: In this 12-week, randomized, placebo-controlled study, we evaluated MET409 - a non-bile acid agonist with a unique chemical scaffold - in patients with NASH. Patients were randomized to receive either 80 mg (n = 20) or 50 mg (n = 19) of MET409, or placebo (n = 19). RESULTS: At Week 12, MET409 lowered liver fat content (LFC), with mean relative reductions of 55% (80 mg) and 38% (50 mg) vs. 6% in placebo (p <0.001). MET409 achieved ≥30% relative LFC reduction in 93% (80 mg) and 75% (50 mg) of patients vs. 11% in placebo (p <0.001) and normalized LFC (≤5%) in 29% (80 mg) and 31% (50 mg) of patients vs. 0% in placebo (p <0.05). An increase in alanine aminotransferase (ALT) was observed with MET409, confounding Week 12 changes from baseline (-25% for 80 mg, 28% for 50 mg). Nonetheless, MET409 achieved ≥30% relative ALT reduction in 50% (80 mg) and 31% (50 mg) of patients vs. 17% in placebo. MET409 was associated with on-target high-density lipoprotein cholesterol decreases (mean changes of -23.4% for 80 mg and -20.3% for 50 mg vs. 2.6% in placebo) and low-density lipoprotein cholesterol (LDL-C) increases (mean changes of 23.7% for 80 mg and 6.8% for 50 mg vs. -1.5% in placebo). Pruritus (mild-moderate) occurred in 16% (50 mg) and 40% (80 mg) of MET409-treated patients. CONCLUSION: MET409 lowered LFC over 12 weeks in patients with NASH and delivered a differentiated pruritus and LDL-C profile at 50 mg, providing the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization. LAY SUMMARY: Activation of the farnesoid X receptor (FXR) is a clinically validated approach for treating non-alcoholic steatohepatitis (NASH), although side effects such as itching or increases in low-density lipoprotein cholesterol are frequently dose-limiting. MET409, an FXR agonist with a unique chemical structure, led to significant liver fat reduction and delivered a favorable side effect profile after 12 weeks of treatment in patients with NASH. These results provide the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced.

Selective estrogen receptor degraders with novel structural motifs induce regression in a tamoxifen-resistant breast cancer xenograft.

Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.

The effect of non-neovascular age-related macular degeneration on face recognition performance.

PURPOSE: There is a well-established research base surrounding face recognition in patients with age-related macular degeneration (AMD). However, much of this existing research does not differentiate between results obtained for 'wet' AMD and 'dry' AMD. Here, we test the hypothesis that face recognition performance is worse in patients with dry AMD compared with visually healthy peers. METHODS: Patients (>60 years of age, logMAR binocular visual acuity 0.7 or better) with dry AMD of varying severity and visually healthy age-related peers (controls) completed a modified version of the Cambridge Face Memory Test (CFMT). Percentage of correctly identified faces was used as an outcome measure for performance for each participant. A 90% normative reference limit was generated from the distribution of CFMT scores recorded in the visually healthy controls. Scores for AMD participants were then specifically compared to this limit, and comparisons between average scores in the AMD severity groups were investigated. RESULTS: Thirty patients (median [interquartile range] age of 76 [70, 79] years) and 34 controls (median age of 70 [64, 75] years) were examined. Four, seventeen and nine patients were classified as having early, intermediate and late AMD (geographic atrophy) respectively. Five (17%) patients recorded a face recognition performance worse than the 90% limit (Fisher's exact test, p = 0.46) set by controls; four of these had geographic atrophy. Patients with geographic atrophy identified fewer faces on average (±SD) (61% ± 22%) than those with early and intermediate AMD (75 ± 11%) and controls (74% ± 11%). CONCLUSIONS: People with dry AMD may not suffer from problems with face recognition until the disease is in its later stages; those with late AMD (geographic atrophy) are likely to have difficulty recognising faces. The results from this study should influence the management and expectations of patients with dry AMD in both community practice and hospital clinics.

Patterns of Binocular Visual Field Loss Derived from Large-Scale Patient Data from Glaucoma Clinics.

PURPOSE: To estimate prevalence of visual field (VF) loss in superior and inferior hemifields in binocular VFs in a large sample of patients with bilateral glaucoma. DESIGN: Retrospective cohort study. PARTICIPANTS: Glaucoma patients and suspects attending 4 regionally different secondary-care eye clinics in the United Kingdom. METHODS: Binocular integrated visual fields (IVFs) using a best location method were constructed for 16 642 patients with bilateral VF loss. A significant VF defect was defined as 3 or more VF locations less than a certain sensitivity threshold, such as 20 dB. Patients were classified as having a VF defect in the inferior hemifield, superior hemifield, both hemifields, or neither hemifield. The criteria for number of locations and sensitivity threshold (in decibels) were varied across a large range of values. In addition, factor analysis was applied to the sensitivity values (in decibels) of the IVFs to determine common defect patterns in an automated fashion. MAIN OUTCOME MEASURES: Ratio of patients with binocular VF defects in the superior compared with the inferior areas of the IVF. RESULTS: Estimates of the ratio of patients having binocular VF defects in the superior compared with the inferior region of the IVF ranged from 2.1 (95% confidence interval, 2.1-2.4) to as high as 5.1 (95% confidence interval, 4.7-5.5), depending on the defect criteria used. Fewer than 10% of those patients exhibiting relatively early binocular VF loss had a defect confined to the inferior region only. Common patterns of binocular VF loss were dominated chiefly by superior hemifield defects. CONCLUSIONS: In a clinical population of patients with measurable VF loss in both eyes, superior-only binocular VF loss is more common than inferior-only loss. These estimates, derived from large collections of electronic medical records, are useful for interpreting findings about location of binocular VF loss impacting everyday activities and examining visual disability in glaucoma.

Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft.

Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.

Eye movements and reading in glaucoma: observations on patients with advanced visual field loss.

PURPOSE: To investigate the relationship between reading speed and eye movements in patients with advanced glaucomatous visual field (VF) defects and age-similar visually healthy people. METHODS: Eighteen patients with advanced bilateral VF defects (mean age: 71, standard deviation [SD]: 7 years) and 39 controls (mean age: 67, SD: 8 years) had reading speed measured using short passages of text on a computer set-up incorporating eye tracking. Scanpaths were plotted and analysed from these experiments to derive measures of 'perceptual span' (total number of letters read per number of saccades) and 'text saturation' (the distance between the first and last fixation on lines of text). Another eye movement measure, termed 'saccadic frequency' (total number of saccades made to read a single word), was derived from a separate lexical decision task, where words were presented in isolation. RESULTS: Significant linear association was demonstrated between perceptual span and reading speed in patients (R (2) = 0.42) and controls (R (2) = 0.56). Linear association between saccadic frequency during the LDT and reading speed was also found in patients (R (2) = 0.42), but not in controls (R (2) = 0.02). Patients also exhibited greater average text saturation than controls (P = 0.004). CONCLUSION: Some, but not all, patients with advanced VF defects read slower than controls using short text passages. Differences in eye movement behaviour may partly account for this variability in patients. These patients were shown to saturate lines of text more during reading, which may explain previously-reported difficulties with sustained reading.

How does glaucoma look?: patient perception of visual field loss.

OBJECTIVE: To explore patient perception of vision loss in glaucoma and, specifically, to test the hypothesis that patients do not recognize their impairment as a black tunnel effect or as black patches in their field of view. DESIGN: Clinic-based cross-sectional study. PARTICIPANTS: Fifty patients (age range, 52-82 years) with visual acuity better than 20/30 and with a range of glaucomatous visual field (VF) defects in both eyes, excluding those with very advanced disease (perimetrically blind). METHODS: Participants underwent monocular VF testing in both eyes using a Humphrey Field Analyzer (HFA; Carl Zeiss Meditec, Dublin, CA; 24-2 Swedish interactive threshold algorithm standard tests) and other tests of visual function. Participants took part in a recorded interview during which they were asked if they were aware of their VF loss; if so, there were encouraged to describe it in their own words. Participants were shown 6 images modified in a variety of ways on a computer monitor and were asked to select the image that most closely represented their perception of their VF loss. MAIN OUTCOME MEASURES: Forced choice of an image best representing glaucomatous vision impairment. RESULTS: Participants had a range of VF defect severity: average HFA mean deviation was -8.7 dB (standard deviation [SD], 5.8 dB) and -10.5 dB (SD, 7.1 dB) in the right and left eyes, respectively. Thirteen patients (26%; 95% confidence interval [CI], 15%-40%) reported being completely unaware of their vision loss. None of the patients chose the images with a distinct black tunnel effect or black patches. Only 2 patients (4%; 95% CI, 0%-14%) chose the image with a tunnel effect with blurred edges. An image depicting blurred patches and another with missing patches was chosen by 54% (95% CI, 39%-68%) and 16% (95% CI, 7%-29%) of the patients, respectively. Content analysis of the transcripts from the recorded interviews indicated a frequent use of descriptors of visual symptoms associated with reported blur and missing features. CONCLUSIONS: Patients with glaucoma do not perceive their vision loss as a black tunnel effect or as black patches masking their field of view. These findings are important in the context of depicting the effects of glaucomatous vision loss and raising awareness for glaucoma detection. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Data on eye movements of glaucoma patients with asymmetrical visual field loss during free viewing.

This paper describes data from Asfaw at al. [1], which examined the eye movements of glaucoma patients (n=15) with pronounced asymmetrical vision loss (visual field loss worse in one eye). This allows for within-subject comparisons between the better and worse eye, thereby controlling for the effects of individual differences between patients. All patients had a clinical diagnosis of open angle glaucoma (OAG). Participants were asked to look at images of nature monocularly (free viewing; fellow eye patched) while gaze was recorded at 1000 Hz using a remote eye tracker (EyeLink 1000). Raw and processed eye tracking data are provided. In addition, clinical (visual acuity, contrast sensitivity and visual field) and demographic information (age, sex) are provided.

Heteroaromatic-aminomethyl quinolones: potent and selective iNOS inhibitors.

The overproduction of nitric oxide during the biological response to inflammation by the nitric oxide synthase (NOS) enzymes have been implicated in the pathology of many diseases. By removal of the amide core from uHTS-derived quinolone 4, a new series highly potent heteroaromatic-aminomethyl quinolone iNOS inhibitors 8 were identified. SAR studies led to identification of piperazine 22 and pyrimidine 32, both of which reduced plasma nitrates following oral dosing in a mouse lipopolysaccharide challenge assay.

Eye movements during visual search in patients with glaucoma.

BACKGROUND: Glaucoma has been shown to lead to disability in many daily tasks including visual search. This study aims to determine whether the saccadic eye movements of people with glaucoma differ from those of people with normal vision, and to investigate the association between eye movements and impaired visual search. METHODS: Forty patients (mean age: 67 [SD: 9] years) with a range of glaucomatous visual field (VF) defects in both eyes (mean best eye mean deviation [MD]: -5.9 (SD: 5.4) dB) and 40 age-related people with normal vision (mean age: 66 [SD: 10] years) were timed as they searched for a series of target objects in computer displayed photographs of real world scenes. Eye movements were simultaneously recorded using an eye tracker. Average number of saccades per second, average saccade amplitude and average search duration across trials were recorded. These response variables were compared with measurements of VF and contrast sensitivity. RESULTS: The average rate of saccades made by the patient group was significantly smaller than the number made by controls during the visual search task (P = 0.02; mean reduction of 5.6% (95% CI: 0.1 to 10.4%). There was no difference in average saccade amplitude between the patients and the controls (P = 0.09). Average number of saccades was weakly correlated with aspects of visual function, with patients with worse contrast sensitivity (PR logCS; Spearman's rho: 0.42; P = 0.006) and more severe VF defects (best eye MD; Spearman's rho: 0.34; P = 0.037) tending to make less eye movements during the task. Average detection time in the search task was associated with the average rate of saccades in the patient group (Spearman's rho = -0.65; P < 0.001) but this was not apparent in the controls. CONCLUSIONS: The average rate of saccades made during visual search by this group of patients was fewer than those made by people with normal vision of a similar average age. There was wide variability in saccade rate in the patients but there was an association between an increase in this measure and better performance in the search task. Assessment of eye movements in individuals with glaucoma might provide insight into the functional deficits of the disease.

Glaucoma and reading: exploring the effects of contrast lowering of text.

PURPOSE: Past research has not fully ascertained the extent to which people with glaucoma have difficulties with reading. This study measures change in reading speed when letter contrast is reduced, to test the hypothesis that patients with glaucoma are more sensitive to letter contrast than age-similar visually healthy people. METHODS: Fifty-three patients with glaucoma [mean age: 66 years (standard deviation: 9)] with bilateral visual field (VF) defects and 40 age-similar visually healthy control subjects [mean age: 69 (standard deviation: 8) years] had reading speeds measured using sets of fixed size, non-scrolling texts on a computer setup that incorporated an eye tracking device. All participants had visual acuity ≥6/9, and they underwent standard tests of visual function including Humphrey 24-2 and 10-2 VFs. Potential non-visual confounders were also tested, including cognitive ability (Middlesex Elderly Assessment of Mental Status Test) and general reading ability. Individual average raw reading speeds were calculated from 8 trials (different passages of text) at both 100% and 20% letter contrast. RESULTS: Patients had an average 24-2 VF MD of -6.5 (range: 0.7 to -17.3) dB in the better eye. The overall median reduction in reading speed due to decreasing the contrast of the text in the patients was 20%, but with considerable between-individual variation (interquartile range, 8%-44%). This reduction was significantly greater (p = 0.01) than the controls [median: 11% (interquartile range, 6%-17%)]. Patients and controls had similar average performance on Middlesex Elderly Assessment of Mental Status Test (p = 0.71), a modified Burt Reading ability test (p = 0.33), and a computer-based lexical decision task (p = 0.53) and had similar self-reported day-to-day reading frequency (p = 0.12). CONCLUSIONS: Average reduction in reading speed caused by a difference in letter contrast between 100% and 20% is significantly more apparent in patients with glaucoma when compared with visually healthy people with a similar age and similar cognitive/reading ability.

Pharmacological characterization of KLYP961, a dual inhibitor of inducible and neuronal nitric-oxide synthases.

Nitric oxide (NO) derived from neuronal nitric-oxide synthase (nNOS) and inducible nitric-oxide synthase (iNOS) plays a key role in various pain and inflammatory states. KLYP961 (4-((2-cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one) inhibits the dimerization, and hence the enzymatic activity of human, primate, and murine iNOS and nNOS (IC(50) values 50-400 nM), with marked selectivity against endothelial nitric-oxide synthase (IC(50) >15,000 nM). It has ideal drug like-properties, including excellent rodent and primate pharmacokinetics coupled with a minimal off-target activity profile. In mice, KLYP961 attenuated endotoxin-evoked increases in plasma nitrates, a surrogate marker of iNOS activity in vivo, in a sustained manner (ED(50) 1 mg/kg p.o.). KLYP961 attenuated pain behaviors in a mouse formalin model (ED(50) 13 mg/kg p.o.), cold allodynia in the chronic constriction injury model (ED(50) 25 mg/kg p.o.), or tactile allodynia in the spinal nerve ligation model (ED(50) 30 mg/kg p.o.) with similar efficacy, but superior potency relative to gabapentin, pregabalin, or duloxetine. Unlike morphine, the antiallodynic activity of KLYP961 did not diminish upon repeated dosing. KLYP961 also attenuated carrageenin-induced edema and inflammatory hyperalgesia and writhing response elicited by phenylbenzoquinone with efficacy and potency similar to those of celecoxib. In contrast to gabapentin, KLYP961 did not impair motor coordination at doses as high as 1000 mg/kg p.o. KLYP961 also attenuated capsaicin-induced thermal allodynia in rhesus primates in a dose-related manner with a minimal effective dose (≤ 10 mg/kg p.o.) and a greater potency than gabapentin. In summary, KLYP961 represents an ideal tool with which to probe the physiological role of NO derived from iNOS and nNOS in human pain and inflammatory states.

An exploratory study of visual search performance in glaucoma.

PURPOSE: Visual search plays an integral role in many daily activities. This study aimed to determine whether patients with glaucoma are slower than visually healthy age-matched individuals when searching for items in computer displayed images. METHODS: Forty participants were recruited for the study: 20 patients with a clinical diagnosis of glaucoma and 20 age-similar visually healthy control subjects. All participants had visual acuity of 6/12 or better. Participants were presented with 20 images with Landolt C symbols and 15 photographic images of everyday scenes on a computer. The time taken by each participant to locate a specified item in each image was recorded. Average search times were calculated across participants and compared between groups. RESULTS: All the patients had visual field defects in both eyes. On average, the patients also differed from control subjects by binocular contrast sensitivity measurements (p = 0.01) and visual acuity (p = 0.003). The patients (mean age = 67 years, S.D.: 10 years) and controls (mean age: 67 years, S.D.: 11 years) were age similar (p = 0.40). The median search time for patients finding target items in photographs of everyday scenes was 15.2 s (interquartile range 9.4-20.6 s) and this was significantly slower than the median time (10.0 s; interquartile range 7.2-10.3 s) taken by the controls (p = 0.007). There was no statistical evidence for a difference in median search times between groups in the Landolt C search task (p = 0.24). CONCLUSION: Some individuals with glaucomatous visual field defects in both eyes find it especially difficult to locate objects in photographs of everyday scenes when compared to visually healthy individuals of a similar age.

Heterocycle-substituted proline dipeptides as potent VLA-4 antagonists.

A variety of N-linked tertiary amines and heteroarylamines were examined at the 4-position of sulfonylated proline dipeptides in order to improve VLA-4 receptor off-rates and overcome the issue of CYP3A4 time-dependent inhibition of ester prodrugs. A tight-binding inhibitor 5j with a long off-rate provided sustained receptor occupancy despite poor oral pharmacokinetics.

Using eye movements to detect visual field loss: a pragmatic assessment using simulated scotoma.

Glaucoma is a leading cause of irreversible sight-loss and has been shown to affect natural eye-movements. These changes may provide a cheap and easy-to-obtain biomarker for improving disease detection. Here, we investigated whether these changes are large enough to be clinically useful. We used a gaze-contingent simulated visual field (VF) loss paradigm, in which participants experienced a variable magnitude of simulated VF loss based on longitudinal data from a real glaucoma patient (thereby controlling for other variables, such as age and general health). Fifty-five young participants with healthy vision were asked to view two short videos and three pictures, either with: (1) no VF loss, (2) moderate VF loss, or (3) advanced VF loss. Eye-movements were recorded using a remote eye tracker. Key eye-movement parameters were computed, including saccade amplitude, the spread of saccade endpoints (bivariate contour ellipse area), location of saccade landing positions, and similarity of fixations locations among participants (quantified using kernel density estimation). The simulated VF loss caused some statistically significant effects in the eye movement parameters. Yet, these effects were not capable of consistently identifying simulated VF loss, despite it being of a magnitude likely easily detectable by standard automated perimetry.

Measuring dynamic levels of self-perceived anxiety and concern during simulated mobility tasks in people with non-neovascular age-related macular degeneration.

BACKGROUND/AIMS: To assess response to real-world mobility scenarios in people with dry age-related macular degeneration (AMD) using a computer-based test. METHODS: Participants were shown 18 point-of-view computer-based movies simulating walking through real-world scenarios, and pressed a button during scenes which would cause them self-perceived anxiety or concern in their day-to-day life. Button pressure was recorded throughout. Pressure traces were generated, which aligned with each movie time point. Group averages based on AMD severity were generated. Bootstrapped confidence intervals (CIs) for responses by group were generated around traces. Traces were examined to discover events causing the greatest differences between groups. RESULTS: Participants had early/no AMD (n=8), intermediate AMD (n=7) or geographic atrophy (n=15 (GA)). Median (IQR) logMAR visual acuity was 0.04 (-0.04, 0.18), 0.26 (0.10, 0.40) and 0.32 (0.20, 0.56), respectively. Participants with intermediate AMD or GA recorded greater pressure than those with early and no AMD (Kruskal-Wallis, p=0.04). Four events involving navigating stairs and three under low luminance elicited greatest differences between groups (p<0.001). CONCLUSION: People with intermediate AMD or GA likely experience higher levels of concern associated with mobility. The test highlights areas of specific concern. Results should be useful in patient management and educating the public about the everyday effects of AMD.

KLYP956 is a non-imidazole-based orally active inhibitor of nitric-oxide synthase dimerization.

Nitric-oxide synthases (NOS) generate nitric oxide (NO) through the oxidation of l-arginine. Inappropriate or excessive production of NO by NOS is associated with the pathophysiology of various disease states. Efforts to treat these disorders by developing arginine mimetic, substrate-competitive NOS inhibitors as drugs have met with little success. Small-molecule-mediated inhibition of NOS dimerization represents an intriguing alternative to substrate-competitive inhibition. An ultra-high-throughput cell-based screen of 880,000 small molecules identified a novel quinolinone with inducible NOS (iNOS) inhibitory activity. Exploratory chemistry based on this initial screening hit resulted in the synthesis of KLYP956, which inhibits iNOS at low nanomolar concentrations. The iNOS inhibitory potency of KLYP956 is insensitive to changes in concentrations of the substrate arginine, or the cofactor tetrahydrobiopterin. Mechanistic analysis suggests that KLYP956 binds the oxygenase domain in the vicinity of the active site heme and inhibits iNOS and neuronal NOS (nNOS) by preventing the formation of enzymatically active dimers. Oral administration of KLYP956 [N-(3-chlorophenyl)-N-((8-fluoro-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-4-methylthiazole-5-carboxamide] inhibits iNOS activity in a murine model of endotoxemia and blocks pain behaviors in a formalin model of nociception. KLYP956 thus represents the first nonimidazole-based inhibitor of iNOS and nNOS dimerization and provides a novel pharmaceutical alternative to previously described substrate competitive inhibitors.

KD5170, a novel mercaptoketone-based histone deacetylase inhibitor, exerts antimyeloma effects by DNA damage and mitochondrial signaling.

Histone deacetylase inhibitors have emerged as promising anticancer drugs. Using an unbiased ultrahigh throughput screening system, a novel mercaptoketone-based histone deacetylase inhibitor series was identified that was optimized to the lead compound, KD5170. KD5170 inhibited the proliferation of myeloma cell lines and the viability of CD138(+) primary myeloma cells by induction of apoptosis, accompanied by an increase of acetylation of histones and activation of caspase-3, caspase-8, and caspase-9. Treatment with KD5170 caused a loss of mitochondrial membrane potential resulting in release of apoptogenic factors such as cytochrome c, Smac, and apoptosis-inducing factor. Furthermore, KD5170 induced oxidative stress and oxidative DNA damage in myeloma cells as evidenced by the up-regulation of heme oxygenase-1 and H2A.X phosphorylation. Combination of KD5170 with proteasome inhibitor bortezomib or tumor necrosis factor-related apoptosis-inducing ligand synergistically enhanced the antimyeloma activity. We further found that resistance of myeloma cells to KD5170 was associated with activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway under treatment with KD5170. Pretreatment with the mitogen-activated protein kinase inhibitor U0126 restored sensitivity to KD5170, suggesting that the combination of KD5170 with U0126 could overcome drug resistance. Growth of myeloma tumor xenografts in KD5170-treated nude mice was significantly inhibited and survival was prolonged. Histone acetylation was increased in spleen and tumor tissues of animals treated with KD5170. Our data indicate that KD5170 has potent antimyeloma activity in vitro and in vivo, which is mediated by DNA damage and mitochondrial signaling and subsequent induction of apoptosis.

KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo.

Histone deacetylase (HDAC) inhibitors have garnered significant attention as cancer drugs. These therapeutic agents have recently been clinically validated with the market approval of vorinostat (SAHA, Zolinza) for treatment of cutaneous T-cell lymphoma. Like vorinostat, most of the small-molecule HDAC inhibitors in clinical development are hydroxamic acids, whose inhibitory activity stems from their ability to coordinate the catalytic Zn2+ in the active site of HDACs. We sought to identify novel, nonhydroxamate-based HDAC inhibitors with potentially distinct pharmaceutical properties via an ultra-high throughput small molecule biochemical screen against the HDAC activity in a HeLa cell nuclear extract. An alpha-mercaptoketone series was identified and chemically optimized. The lead compound, KD5170, exhibits HDAC inhibitory activity with an IC50 of 0.045 micromol/L in the screening biochemical assay and an EC50 of 0.025 micromol/L in HeLa cell-based assays that monitor histone H3 acetylation. KD5170 also exhibits broad spectrum classes I and II HDAC inhibition in assays using purified recombinant human isoforms. KD5170 shows significant antiproliferative activity against a variety of human tumor cell lines, including the NCI-60 panel. Significant tumor growth inhibition was observed after p.o. dosing in human HCT-116 (colorectal cancer), NCI-H460 (non-small cell lung carcinoma), and PC-3 (prostate cancer) s.c. xenografts in nude mice. In addition, a significant increase in antitumor activity and time to end-point occurred when KD5170 was combined with docetaxel in xenografts of the PC-3 prostate cancer cell line. The biological and pharmaceutical profile of KD5170 supports its continued preclinical and clinical development as a broad spectrum anticancer agent.

Portable Perimetry Using Eye-Tracking on a Tablet Computer-A Feasibility Assessment.

PURPOSE: Visual field (VF) examination by standard automated perimetry (SAP) is an important method of clinical assessment. However, the complexity of the test, and its use of bulky, expensive equipment makes it impractical for case-finding. We propose and evaluate a new approach to paracentral VF assessment that combines an inexpensive eye-tracker with a portable tablet computer ("Eyecatcher"). METHODS: Twenty-four eyes from 12 glaucoma patients, and 12 eyes from six age-similar controls were examined. Participants were tested monocularly (once per eye), with both the novel Eyecatcher test and traditional SAP (HFA SITA standard 24-2). For Eyecatcher, the participant's task was to simply to look at a sequence of fixed-luminance dots, presented relative to the current point of fixation. Start and end fixations were used to determine locations where stimuli were seen/unseen, and to build a continuous map of sensitivity loss across a VF of approximately 20°. RESULTS: Eyecatcher was able to clearly separate patients from controls, and the results were consistent with those from traditional SAP. In particular, mean Eyecatcher scores were strongly correlated with mean deviation scores (r2 = 0.64, P < 0.001), and there was good concordance between corresponding VF locations (∼84%). Participants reported that Eyecatcher was more enjoyable, easier to perform, and less tiring than SAP (all P < 0.001). CONCLUSIONS: Portable perimetry using an inexpensive eye-tracker and a tablet computer is feasible, although possible means of improvement are suggested. TRANSLATIONAL RELEVANCE: Such a test could have significant utility as a case finding device.