Prevalence and Risk Factors for High-Risk Human Papillomavirus Infection and Cervical Disorders: Baseline Findings From an Human Papillomavirus Cohort Study.

BACKGROUND: A persistent infection by high-risk human papillomavirus (HR-HPV) is a prerequisite for the development of cervical neoplasms; however, most studies have focused on risk factors associated with HPV-16 and HPV-18 only. OBJECTIVES: We assessed the association of risk factors with the prevalence of HPV-16, HPV-18, and non-16/18 HR-HPV infection and with the occurrence of cervical lesions in the baseline of a cohort study of HPV persistence in a Mexican population. METHODS: Cross-sectional study within the baseline of a 5-year dynamic cohort study of HR-HPV persistence in women with an abnormal cytology study result from 2015 to 2021. HPV DNA was detected using the Anyplex II HPV 28 kit. Data on lifestyle, sociodemographic, and reproductive factors were assessed using bivariate and multivariate analyses to determine the association of risk factors with HR-HPV infection status and histopathologic diagnosis. RESULTS: A total of 373 women were included in the study. The overall prevalence of HR-HPV infection was 69.97%. The most prevalent HR-HPV genotypes, including single and multiple infections, were HPV-53 (13.4%), HPV-16 (11.8%), HPV-58 (10.9%), HPV-31 (10.9%), and HPV-66 (10.7%). We found 90 multiple HR-HPV infection patterns, all of them with α-6 and -9 species. Significant associations of multiple HPV-16 and non-16/18 HR-HPV infections were found with marital status, number of lifetime sexual partners, and smoking history. The most prevalent genotype in CIN1 and CIN2 patients was HPV-16. No association was found between biological plausibility risk factors and cervical lesions. CONCLUSIONS: The risk factors for non-16/18 HR-HPV multiple infections are no different than those linked to HPV-16 multiple infections.

Development and Characterization of a Non-Thermal Plasma Source for Therapeutic Treatments.

OBJECTIVE: an innovative non-thermal plasma (NTP) system constituted by a radiofrequency (RF) power generator directly coupled to a treatment probe is described and characterized. This system is intended to be applied as a medical device for therapeutic treatments. METHODS: electrical characterization of the radiofrequency power generator supplying the treatment probe was performed. Meanwhile, generated NTP was optically analyzed. Obtained data were studied to establish the safety profile of plasma application on heat sensitive matter. RESULTS: the NTP system was validated through bacterial deactivation trials, as well as, of being capable of deactivating carcinogenic cells. Besides promoting and accelerating wound closure in vivo performed in mice, demonstrating faster healing than that done with conventional treatments. CONCLUSION: the NTP system's characterization is an essential stage to determine the adequate application of the generated plasma over organic media. The therapeutic benefits of the NTP system were proved by the development of in vivo experiences involving laboratory mice. SIGNIFICANCE: the generated NTP interacts with surrounding air particles producing reactive oxygen and nitrogen species, which, exhibit bactericidal and antiseptic effects due to their strong biochemical reactivity; functioning like critical mediators in animal physiology and promoting wound healing processes. These properties make the NTP system a feasible technology intended for therapeutic treatments.

Low cigarette smoking prevalence in peri-urban Peru: results from a population-based study of tobacco use by self-report and urine cotinine.

BACKGROUND: A recent study found lower self-reported prevalence of tobacco smoking in a peri-urban area of Lima, Peru than previously reported in urban samples. These regions encompass substantial proportions of Peru's population - ones at greater risk of disease due to reduced healthcare access - but have been less often studied. We validate low smoking prevalence with urine cotinine and characterize chronic disease and lung function outcomes between non-, occasional, and daily smokers. METHODS: Data are from the CRONICAS Cohort Study, a population-based longitudinal study in four low-resource Peruvian settings, which began in 2010. Of a baseline cohort of 2978 adults, we prospectively followed 2583 (87%) to determine prevalence of chronic illness. RESULTS: In a baseline sub-sample of 382 participants, median adjusted cotinine was 0.0 mcg/mg (IQR 0-0) for both self-reported non-smokers and occasional smokers compared to 172.3 mcg/mg (IQR 0-709.2) for daily smokers. Creatinine-adjusted cotinine validated daily smoking prevalence of 4.7% at a cutoff of 100 mcg/mg. Kappa statistic for daily smoking and creatinine- adjusted cotinine ≥100 mcg/mg was 0.65 (95% CI 0.47, 0.83), indicating substantial agreement. At baseline, we found 3.3% daily and 8.9% occasional smoking by self-report for the full cohort. Follow-up indicated little difference in chronic disease prevalence between groups. Daily smokers trended toward having a greater decline in FVC (-1%; 95% CI -2.9, 0.8) and FEV1 (-1.3%; 95% CI -3.2, 0.6) over 40 months when compared to non-smokers, whereas the decline in lung function for occasional smokers was similar compared to non-smokers (-0.2% FVC; 95% CI -1.5, 1.0) and (0% FEV1; 95% CI -1.3, 1.3). CONCLUSIONS: Our data places Peru within a previously-described pattern of smoking found in much of Latin America, favoring occasional over daily smoking and low cigarette consumption. We determine that there are not significant differences between smoking groups concerning chronic disease outcomes. We favor distinguishing between daily and occasional smokers in order to accurately characterize these low-use populations.

Identifying biomarkers for asthma diagnosis using targeted metabolomics approaches.

BACKGROUND: The diagnosis of asthma in children is challenging and relies on a combination of clinical factors and biomarkers including methacholine challenge, lung function, bronchodilator responsiveness, and presence of airway inflammation. No single test is diagnostic. We sought to identify a pattern of inflammatory biomarkers that was unique to asthma using a targeted metabolomics approach combined with data science methods. METHODS: We conducted a nested case-control study of 100 children living in a peri-urban community in Lima, Peru. We defined cases as children with current asthma, and controls as children with no prior history of asthma and normal lung function. We further categorized enrollment following a factorial design to enroll equal numbers of children as either overweight or not. We obtained a fasting venous blood sample to characterize a comprehensive panel of targeted markers using a metabolomics approach based on high performance liquid chromatography-mass spectrometry. RESULTS: A statistical comparison of targeted metabolites between children with asthma (n = 50) and healthy controls (n = 49) revealed distinct patterns in relative concentrations of several metabolites: children with asthma had approximately 40-50% lower relative concentrations of ascorbic acid, 2-isopropylmalic acid, shikimate-3-phosphate, and 6-phospho-d-gluconate when compared to children without asthma, and 70% lower relative concentrations of reduced glutathione (all p < 0.001 after Bonferroni correction). Moreover, a combination of 2-isopropylmalic acid and betaine strongly discriminated between children with asthma (2-isopropylmalic acid ≤ 13 077 normalized counts/second) and controls (2-isopropylmalic acid > 13 077 normalized counts/second and betaine ≤ 16 47 121 normalized counts/second). CONCLUSIONS: By using a metabolomics approach applied to serum, we were able to discriminate between children with and without asthma by revealing different metabolic patterns. These results suggest that serum metabolomics may represent a diagnostic tool for asthma and may be helpful for distinguishing asthma phenotypes.

Cervical Microbiome and Cytokine Profile at Various Stages of Cervical Cancer: A Pilot Study.

Cervical cancer (CC) is caused by high-risk human papillomavirus persistence due to the immunosuppressive tumor microenvironment mediated by cytokines. Vaginal microbiota determines the presence of certain cytokines locally. We assessed the association between cervical microbiota diversity and the histopathological diagnosis of each stage of CC, and we evaluated mRNA cervical expression levels of IL-4, IL-6, IL-10, TGF-ß1, TNF-α and IFN-γ across the histopathological diagnosis and specific bacterial clusters. We determined the cervical microbiota by high throughput sequencing of 16S rDNA amplicons and classified it in community state types (CST). Mean difference analyses between alpha-diversity and histopathological diagnosis were carried out, as well as a ß-diversity analysis within the histological diagnosis. Cervical cytokine mRNA expression was analyzed across the CSTs and the histopathological diagnoses. We found a significant difference in microbiota's diversity in NCL-HPV negative women vs those with squamous intraepithelial lesions (SIL) and CC(p = 0.006, p = 0.036).When ß-diversity was evaluated, the CC samples showed the highest variation within groups (p<0.0006) and the largest distance compared to NCL-HPV negative ones (p<0.00001). The predominant bacteria in women with normal cytology were L. crispatus and L. iners, whereas for SIL, it was Sneathia spp. and for CC, Fusobacterium spp. We found higher median cervical levels of IL-4 and TGF-ß1 mRNA in the CST dominated by Fusobacterium spp. These results suggest that the cervical microbiota may be implicated in cervical cancer pathology. Further cohort studies are needed to validate these findings.

Association of Roadway Proximity with Indoor Air Pollution in a Peri-Urban Community in Lima, Peru.

The influence of traffic-related air pollution on indoor residential exposure is not well characterized in homes with high natural ventilation in low-income countries. Additionally, domestic allergen exposure is unknown in such populations. We conducted a pilot study of 25 homes in peri-urban Lima, Peru to estimate the effects of roadway proximity and season on residential concentrations. Indoor and outdoor concentrations of particulate matter (PM2.5), nitrogen dioxide (NO2), and black carbon (BC) were measured during two seasons, and allergens were measured in bedroom dust. Allergen levels were highest for dust mite and mouse allergens, with concentrations above clinically relevant thresholds in over a quarter and half of all homes, respectively. Mean indoor and outdoor pollutant concentrations were similar (PM2.5: 20.0 vs. 16.9 µg/m³, BC: 7.6 vs. 8.1 µg/m³, NO2: 7.3 vs. 7.5 ppb), and tended to be higher in the summer compared to the winter. Road proximity was significantly correlated with overall concentrations of outdoor PM2.5 (rs = -0.42, p = 0.01) and NO2 (rs = -0.36, p = 0.03), and outdoor BC concentrations in the winter (rs = -0.51, p = 0.03). Our results suggest that outdoor-sourced pollutants significantly influence indoor air quality in peri-urban Peruvian communities, and homes closer to roadways are particularly vulnerable.

Association Between Serum 25-Hydroxy Vitamin D Levels and Blood Pressure Among Adolescents in Two Resource-Limited Settings in Peru.

INTRODUCTION: Serum 25-hydroxyvitamin D (25OHD) deficiency (<50 nmol/l or 20 ng/ml) has been associated with increased blood pressure (BP) in observational studies. A paucity of data on this relationship is available in Latin American or child populations. This study investigates the association between 25OHD levels and BP in adolescents at risk for vitamin D deficiency in 2 Peruvian settings. METHODS: In a population-based study of 1,441 Peruvian adolescents aged 13-15 years, 1,074 (75%) provided a serum blood sample for 25OHD analysis and BP measurements. Relationships between 25OHD and BP metrics were assessed using multiple linear regressions, adjusted for anthropometrics and sociodemographic factors. RESULTS: 25OHD deficiency was associated with an elevated diastolic BP (DBP) (1.09 mm Hg increase, 95% confidence interval: 0.04 to 2.14; P = 0.04) compared to nondeficient adolescents. Systolic BP (SBP) trended to increase with vitamin D deficiency (1.30 mm Hg increase, 95% confidence interval: -0.13 to 2.72; P = 0.08). Mean arterial pressure (MAP) was also greater in adolescents with 25OHD (1.16 mm Hg increase, 95% confidence interval: 0.10 to 2.22; P = 0.03). SBP was found to demonstrate a U-shaped relationship with 25OHD, while DBP and MAP demonstrated inverse J-shaped relationships with serum 25OHD status. The association between 25OHD deficiency and BP was not different across study sites (all P ≥ 0.19). DISCUSSION: Adolescents deficient in 25OHD demonstrated increased DBP and MAP and a trend toward increased SBP, when compared to nondeficient subjects. 25OHD deficiency early in life was associated with elevated BP metrics, which may predispose risk of hypertension later in adulthood.

Increased gene copy number of VAMP7 disrupts human male urogenital development through altered estrogen action.

Despite the fact that genitourinary defects are among the most common birth defects in newborns, little is known about their etiology. Here we analyzed children born with congenital genitourinary tract masculinization disorders by array-comparative genomic hybridization, which revealed in 1.35% of cases the presence of de novo copy number gains at Xq28 encompassing the VAMP7 gene, which encodes a vesicle-trafficking protein that is part of the SNARE complex. Transgenic mice carrying a bacterial artificial chromosome encoding human VAMP7 mimicked the defective urogenital traits observed in boys with masculinization disorders such as cryptorchidism, urethral defects and hypospadias. Transgenic mice also exhibited reduced penile length, focal spermatogenic anomalies, diminished sperm motility and subfertility. VAMP7 colocalized with estrogen receptor α (ESR1) in the presence of its cognate ligand, 17ß-estradiol. Elevated levels of VAMP7 markedly intensified ESR1-potentiated transcriptional activity by increasing ESR1 protein cellular content upon ligand stimulation and upregulated the expression of estrogen-responsive genes including ATF3, CYR61 and CTGF, all of which have been implicated in human hypospadias. Hence, increased gene dosage of VAMP7, and thus higher expression levels of its protein product, enhances estrogen receptor action in male genitourinary tissues, affects the virilization of the reproductive tract and results in genitourinary birth defects in humans.

Depresión y ansiedad estado/rasgo en internosadscritos al Programa de Inducción al Tratamiento Penitenciario en Bucaramanga, Colombia / Depressão e ansiedade estado/traço em presos adscritos ao Programa de Indução para o Tratamento Penitenciário em Bucaramanga, Colômbia / Depression and anxiety, state/feature among inmates assigned to the “Induction to Treatment in Prison Program” in Bucaramanga, Colombia

El artículo describe las características de la depresión y la ansiedad estado/rasgo y su prevalencia en internos adscritos al “Programa de Inducción al Tratamiento Penitenciario” del Instituto Nacional Penitenciario y Carcelario –INPEC– en Bucaramanga, Colombia. La muestra comprendió 112 internos con un promedio de edad de 33 años, a quienes se les aplicó el Inventario de Depresión Estado Rasgo (IDER) y el Inventario de Ansiedad Estado Rasgo (STAI). Los resultados indican que un 43,1% realizó su primera transgresión a la norma entre los 8 y 18 años, y un 74,1% presentó consumo de sustancias psicoactivas, mientras los registros de manifestaciones depresivas revelan que el 16,7% la califi có como estado y un 43,68% como rasgo. Por su parte, la afectación ansiosa se mostró en un 8,03% como estado y en un 85,7% como rasgo.De acuerdo con esto, hubo mayor proporción de personas con experiencias previas que desarrollaron cuadros sintomatológicos, que aquellas en las que la situación de encarcelamiento constituye un causante o detonante.

This article describes the characteristic manifestations of the depression and anxiety state/feature, and their prevalence among inmates assigned to the “Programa de Inducción al Tratamiento Penitenciario” (Induction to the Treatment in Prison Program) of the INPEC, the National Penitentiary and Prison Institute at Bucaramanga, Colombia.The sample included 112 inmates with an average age of 33 years to whom the Depression State/Feature Inventory (known as IDER in Colombia) and the Anxiety State/Feature Inventory (known as STAI in Colombia) were applied. The results show that 43.1% of the inmates committed their first off ense between 8 and 18 years of age, and 74.1% had used psychoactive substances, while the records of depressive manifestations reveal that 16.7% rated them as a state, and 43.68% as a feature. On the other hand, in 8.03% of the cases, anxiety was shown as a state, and in 85.7% as a feature. According to this, the ratio of individuals with previous experiences having developed a symptomatology was higher than those where the imprisonment situation is a cause or a triggering factor.

O artigo descreve as características da depressão e a ansiedade estado/traço e sua prevalência em presos adscritos ao “Programa de Indução para o Tratamento Penitenciário” do Instituto Nacional Penitenciario y Carcelario -INPEC em Bucaramanga, Colômbia. A amostra incluiu 112 presos com idade média de 33 anos, que receberam o Inventário de Depressão Estado Rasgo (IDER) e o Inventário de Ansiedade Estado Rasgo (STAI). Os resultados indicam que 43,1% realizou sua primeira transgressão à norma entre 8 e 18 anos de idade, e um 74,1% apresentou consumo de substâncias psicoativas, enquanto os registros das manifestações depressivas revelam que 16,7% atribuíram como estado e 43,68% como rasgo. Por outro lado, a afetação ansiosa mostrou 8,03% como estado e 85,7% como rasgo. De acordo com isso, houve maior proporção de pessoas com experiências anteriores, que desenvolveram os quadros sintomatológicos, do que aqueles em que a situação de detenção constitui uma causa ou um detonante.

Extrofia vesical en un neonato y su relación con otras malformaciones congénitas / Bladder exstrophy in a newborn and its relationship with other congenital defects

Antecedentes: La extrofia vesical una entidad rara que ocurre en 1:10-50,000 niño, es un defecto grave del cierre de la pared abdominal fetal, el espectro del defecto va desde la epispadia hasta la extrofia de cloaca. Caso clínico: Recién nacido masculino que presenta hernia inguino-escrotal y agenesia del dedo pulgar izquierdo, se le realizó ultrasonido de abdomen, encontrándose agenesia renal derecha y diástasis congénita del hueso púbico, mostrando además la ecocardiografía cardiopatía cianótica congénita con doble cámara desalida de ventrículo derecho, comunicación interventricular perimenbranosa subaórtica, estenosis leve de válvula pulmonar y comunicación interauricular tipo ostium secundum. El abordaje fue multidisciplinario y se realizó intervención quirúrgica de la extrofia vesical a los 42 días deedad. Conclusión: en la actualidad, con el progreso de la tectonología, la mayoría de malformaciones congénitas pueden ser diagnosticadas en el periodo prenatal, de ahí la necesidad del control prenatal, que los ultrasonidos sean realizados por personal calificado, o la incorporación de otras pruebas precisas, como la α-fetoproteína. La reparación de la extrofia vesical requiere experiencia para disminuir la alta morbimortalidad neonatal asociada a esta causa, pero hay que considerar también, que se puede acompañar de otras malformaciones internas, por lo que se requiere evaluación multidisplinaria de estos pacientes para su detección y manejo oportuno. A continuación se describe el segundo caso reportado en la literatura hondureña de extrofia vesical.

The SNP at -592 of human IL-10 gene is associated with serum IL-10 levels and increased risk for human papillomavirus cervical lesion development.

BACKGROUND: Women with Human Papilloma Virus (HPV) persistence are characterized by high levels of IL-10 at cervix. We have determined whether polymorphisms of IL-10 gene promoter might be associated with increased risk of squamous intraepithelial cervical lesions (SICL) and whether exist significative differences of IL-10 mRNA expression at cervix and systemic and serum IL-10 protein between SICL cases and non-Cervical Lesions (NCL). METHODS: Peripheral blood samples from SICL (n = 204) and NCL (n = 166) were used to detect IL-10 promoter polymorphisms at loci -592A/C (rs1800872), -819C/T (rs1800871), -1082A/G (rs1800896), -1352A/G (rs1800893), by allelic discrimination and to evaluate serum IL-10 protein. Cervical epithelial scrapings from NCL and biopsies from SICLs were used for HPV-typing and to evaluate IL-10 mRNA expression level. The systemic and local IL-10 mRNA expression levels were measured by real time-PCR. Genotypic and allelic frequencies of the selected polymorphisms were analyzed by logistic regression, adjusting by age and HPV-genotype, to determine the association with SICL. RESULTS: No significant differences were found between genotype frequencies at loci -819, -1082, and -1352. Individuals carrying at least one copy of risk allele A of polymorphism -592 had a two-fold increased risk of developing SICL [adjusted odds ratio (OR), 2.02 (95% CI, 1.26-3.25), p = 0.003], compared to NCL. The IL-10 mRNA expression and serum IL-10 protein, were significantly higher in SICL cases (p < 0.01), being higher in patients carrying the risk allele A. CONCLUSIONS: The -592 polymorphism is associated with increased risk of SICL and can serve as a marker of genetic susceptibility to SICL among Mexican women. According to IL-10 levels found in SICL, IL-10 can be relevant factor for viral persistence and progression disease.

Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors.

mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.

The discovery and optimization of a novel class of potent, selective, and orally bioavailable anaplastic lymphoma kinase (ALK) inhibitors with potential utility for the treatment of cancer.

A class of 2-acyliminobenzimidazoles has been developed as potent and selective inhibitors of anaplastic lymphoma kinase (ALK). Structure based design facilitated the rapid development of structure-activity relationships (SAR) and the optimization of kinase selectivity. Introduction of an optimally placed polar substituent was key to solving issues of metabolic stability and led to the development of potent, selective, orally bioavailable ALK inhibitors. Compound 49 achieved substantial tumor regression in an NPM-ALK driven murine tumor xenograft model when dosed qd. Compounds 36 and 49 show favorable potency and PK characteristics in preclinical species indicative of suitability for further development.

Effect of urbanisation on asthma, allergy and airways inflammation in a developing country setting.

BACKGROUND: Asthma is a growing public health problem in developing countries. However, few studies have studied the role of urbanisation in this phenomenon. It was hypothesised that children living in a peri-urban setting in Peru have higher rates of asthma and allergy than rural counterparts. METHODS: 1441 adolescents aged 13-15 years were enrolled from two settings: a peri-urban shanty town in Lima (n = 725) and 23 rural villages in Tumbes (n = 716). Participants filled in questionnaires on asthma and allergy symptoms, environmental exposures and sociodemographics, and underwent spirometry, and exhaled nitric oxide (eNO) and allergy skin testing. Indoor particulate matter (PM) concentrations were measured in 170 households. RESULTS: Lima adolescents had higher rates of lifetime wheezing (22% vs 10%), current asthma symptoms (12% vs 3%) and physician-diagnosed asthma (13% vs 2%; all p <0.001). Current rhinitis (23% vs 12%), eczema (12% vs 0.4%), atopy (56% vs 38%), personal history of cigarette smoking (7.4% vs 1.3%) and mean indoor PM (31 vs 13 µg/m(3)) were also higher in Lima (all p < 0.001). The peri-urban environment of Lima was associated with a 2.6-fold greater odds (95% CI 1.3 to 5.3) of asthma in multivariable regression. Forced expiratory volumes were higher and FEV(1)/FVC (forced expiratory volume in 1 s/forced vital capacity) ratios were lower in Lima (all p < 0.001). Higher eNO values in Lima (p < 0.001) were attributable to higher rates of asthma and atopy. CONCLUSIONS: Peri-urban adolescents had more asthma, atopy and airways inflammation and were exposed to more indoor pollution. The findings provide evidence of the risks posed to lung health by peri-urban environments in developing countries.

Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines.

In mammalian cells, the aurora kinases (aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy. AMG 900 is an orally bioavailable, potent, and highly selective pan-aurora kinase inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.

Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine aurora kinase inhibitor.

The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.