PDE6D Inhibitors with a New Design Principle Selectively Block K-Ras Activity

The trafficking chaperone PDE6D (also referred to as PDE delta) has been nominated as a surrogate target for K-Ras4B (hereafter K-Ras). Arl2-assisted unloading of K-Ras from PDE6D in the perinuclear area is significant for correct K-Ras localization and therefore activity. However, the unloading mechanism also leads to the undesired ejection of PDE6D inhibitors. To counteract ejection, others have recently optimized inhibitors for picomolar affinities; however, cell penetration generally seems to remain an issue. To increase resilience against ejection, we engineered a "chemical spring" into prenyl-binding pocket inhibitors of PDE6D. Furthermore, cell penetration was improved by attaching a cell-penetration group, allowing us to arrive at micromolar in cellulo potencies in the first generation. Our model compounds, Deltaflexin-1 and -2, selectively disrupt K-Ras, but not H-Ras membrane organization. This selectivity profile is reflected in the antiproliferative activity on colorectal and breast cancer cells, as well as the ability to block sternness traits of lung and breast cancer cells. While our current model compounds still have a low in vitro potency, we expect that our modular and simple inhibitor redesign could significantly advance the development of pharmacologically more potent compounds against PDE6D and related targets, such as UNC119 in the future

PDE6D Inhibitors with a New Design Principle Selectively Block K-Ras Activity

The trafficking chaperone PDE6D (also referred to as PDE?) has been nominated as a surrogate target for K-Ras4B (hereafter K-Ras). Arl2-assisted unloading of K-Ras from PDE6D in the perinuclear area is significant for correct K-Ras localization and therefore activity. However, the unloading mechanism also leads to the undesired ejection of PDE6D inhibitors. To counteract ejection, others have recently optimized inhibitors for picomolar affinities; however, cell penetration generally seems to remain an issue. To increase resilience against ejection, we engineered a "chemical spring" into prenyl-binding pocket inhibitors of PDE6D. Furthermore, cell penetration was improved by attaching a cell-penetration group, allowing us to arrive at micromolar in cellulo potencies in the first generation. Our model compounds, Deltaflexin-1 and -2, selectively disrupt K-Ras, but not H-Ras membrane organization. This selectivity profile is reflected in the antiproliferative activity on colorectal and breast cancer cells, as well as the ability to block stemness traits of lung and breast cancer cells. While our current model compounds still have a low in vitro potency, we expect that our modular and simple inhibitor redesign could significantly advance the development of pharmacologically more potent compounds against PDE6D and related targets, such as UNC119 in the future

Linear growth and neurodevelopmental outcome of children with congenital hypothyroidism detected by neonatal screening: A controlled study

Introduction: Different growth and neuro-developmental outcomes have been associated with different doses of thyroxine given to infants with congenital hypothyroidism (CH). Materials and Methods: We studied the longitudinal growth pattern and assessed the neurodevelopment of 45 children with CH(25 girls, 20 boys) diagnosed through the national screening program in Qatar, for 6 years or more to examine the effects of initial T4 dosage (50 μg/day) with adjustment of T4 dose to maintain serum free T4 concentrations within the upper quartile of normal range and thyroid stimulating hormone < 4 mIU/mLThe birth size of newborns with CH diagnosed through the screening program before January 2003, was recorded and their growth in weight and stature was monitored every 3 months for at least 6 years of life. The IQ of children was assessed between 3 and 6 years of age using The Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Results: Birth weight, length, and head circumference of patients (3.21 ± 0.43 kg, 50.5 ± 3.21 cm and 34.1 ± 1.5 cm, respectively) did not differ than those for 10,560 normal newborns with normal thyroid function (3.19 ± 0.59 kg, 50.5 ± 2.2 cm and 34.2 ± 1.7 cm). During the first year CH children growth (25.8 ± 2.8 cm/year) was similar to those for normal infants (25.5 ± 0.75 cm/year). During the first 6 years, stature growth was normal in all children with CH versus Center for disease control and prevention (CDC) data. The mean height standard deviation score (HtSDS) of children with CH showed adjustment (± 0.5 SD) toward their mid-parental height SDS (MPHtSDS) only during the second year of life. The children′s mean HtSDS was higher by an average of 0.4 SD between the 2 nd and 7 th year of life. Conclusion: These data proved that effective screening and treatment completely assures normal neurodevelopment and linear growth in patients with CH. The data showed that their HtSDS slightly exceeds their MPHtSDS during childhood

Stability of the Phosphotriester PDE6D Inhibitors

peer reviewedAbstract The kinetics for the cleavage of the phosphotriester PDE6D inhibitors 1 (Deltaflexin-2) and 3 (Deltaflexin-1) and their derivatives 2, 4 and 5 is presented under various conditions in aqueous solutions. The conversion of the phosphotriesters (1?5) into the phosphodiesters 1**?5** was detected to take place as a major degradation process. In the absence of enzyme, the 4-acetylthio-2,2-dimethyl-3-oxobutyl protected compounds (1, 4 and 5) are one order of magnitude more stable than the 4-acetylthio-2-ethoxycarbonyl-3-oxo-2-methylbutyl protected ones (2 and 3). In cell culture (DMEM) containing fetal bovine serum and l-glutamine, an intermediary formation of S?S-dimer competed with the removal of the protecting group after deacetylation of the starting material. In addition, the susceptibility of the compounds to amine nucleophiles as well as their stability under acidic and basic condition were determined in non-aqueous solutions

Does priming with sex steroids improve the diagnosis of normal growth hormone secretion in short children?

Introduction: There is still controversy for priming with sex steroid before growth hormone (GH) testing. Objective: We studied GH response to stimulation in 92 children >9 years with idiopathic short stature (height standard deviation score [HtSDS]-2). They were divided randomly into two groups. Children in Group 1 (n = 50) were primed with premarin in girls and testosterone in boys and those in Group 2 were not primed (n = 42). All children were tested using standard clonidine test and their serum insulin-like growth factor-I concentration (IGF-I). Additionally the growth and GH-IGF-I data of the two groups of children were compared with those for 32 short children (HtSDS 9 years. The peak GH response to clonidine provocation test did not differ before (n = 42) versus after 9 years (n = 32) of age. Conclusions: In this randomized study priming with sex steroids before GH testing did not significantly increase the yield of diagnosing short patients with normal GH secretion. In addition, GH response to provocation did not vary significantly between young (9 years) short children

Recent Advancements in the Development of Anti-Breast Cancer Synthetic Small Molecules

Among all cancer types, breast cancer (BC) still stands as one of the most serious diseases responsible for a large number of cancer-associated deaths among women worldwide, and diagnosed cases are increasing year by year worldwide. For a very long time, hormonal therapy, surgery, chemotherapy, and radiotherapy were used for breast cancer treatment. However, these treatment approaches are becoming progressively futile because of multidrug resistance and serious side effects. Consequently, there is a pressing demand to develop more efficient and safer agents that can fight breast cancer belligerence and inhibit cancer cell proliferation, invasion and metastasis. Currently, there is an avalanche of newly designed and synthesized molecular entities targeting multiple types of breast cancer. This review highlights several important synthesized compounds with promising anti-BC activity that are categorized according to their chemical structures

Discovery of 3,6-disubstituted pyridazines as a novel class of anticancer agents targeting cyclin-dependent kinase 2: synthesis, biological evaluation and in silico insights

Human health in the current medical era is facing numerous challenges, especially cancer. So, the therapeutic arsenal for cancer should be unremittingly enriched with novel small molecules that selectively target tumour cells with minimal toxicity towards normal cells. In this context, herein a new series of 3,6-disubstituted pyridazines 11a–r has been synthesised and evaluated for in vitro anticancer activity. They possessed good anti-proliferative action towards human breast cancer T-47D (IC50 range: 0.43 ± 0.01 − 35.9 ± 1.18 µM) and MDA-MB-231 (IC50 range: 0.99 ± 0.03 − 34.59 ± 1.13 µM) cell lines, whereas they displayed weak activity against the tested ovarian cancer cell line SKOV-3. Among the studied compounds, the methyltetrahydropyran-bearing pyridazine 11m emerged as the unique submicromolar growth inhibitor herein reported towards both T-47D (IC50 = 0.43 ± 0.01 µM) and MDA-MB-231 (IC50 = 0.99 ± 0.03 µM) cell lines. In addition, the biological results indicated that pyridazines 11l and 11m exerted an efficient alteration within the cell cycle progression as well as induction of apoptosis in both T-47D and MDA-MB-231 cells. Moreover, pyridazines 11l and 11m displayed good mean tumour S. I. values of 13.7 and 16.1 upon assessment of their cytotoxicity towards non-tumorigenic breast MCF-10A cells. Furthermore, an in silico study proposed CDK2 as a probable enzymatic target for pyridazines 11, and explored their binding interactions within the vicinity of CDK2 binding site. Subsequently, pyridazines 11e, 11h, 11l, and 11m were selected to be evaluated for their ability to inhibit CDK2, where they exerted good inhibitory activity (IC50 = 151, 43.8, 55.6 and 20.1 nM, respectively). Finally, the in silico study implied that target pyridazines 11 exhibited not only an efficient anticancer activity but also an acceptable ADME, physicochemical and druglikeness properties, specifically pyridazines 11l and 11m. Overall the obtained results from this study quite sustained our strategy and gave us a robust opportunity for further development and optimisation of 3,6-disubstituted pyridazine scaffold to enrich therapeutic arsenal with efficient and safe anticancer CDK inhibitors

Epidemiological and Clinical Characteristics of Streptococcus pneumoniae Infections in a Tertiary Care Center in Bahrain (2010-2014)

Objective: To describe the epidemiology of invasive and non-invasive pneumococcal disease during a 5-year period in a major hospital in Bahrain. &nbsp; Design and Setting: Retrospective study of cases of pneumococcal diseases among patient ≥ 14 years old during a five-year period (2010-2014), who attended Salmaniya Medical Complex, Bahrain. &nbsp; Patients and Methods: Laboratory data was obtained on Streptococcus pneumoniae isolates. Patients ≥14 years old of age, both inpatient and outpatient with cultures positive for Streptococcus pneumoniae were included. Only samples from blood, cerebrospinal fluid (CSF), pleural fluid, sputum, deep tracheal aspirate (DTA), bronchial wash,&nbsp;eye discharge and middle ear fluid were included. Demographics and clinical records from medical files were then reviewed. &nbsp; Results: A total of 130 culture samples met the inclusion criteria and were analyzed. One-hundred twenty-six patients with pneumococcal disease were identified; with 65% being non-invasive and 35% being invasive pneumococcal disease. Overall, non-bacteremic Pneumonia was the most frequent manifestation, followed by bacteremia. Pneumococcal disease was more common among male patients (62.7%). Mean age was 57.67 (15-95 years). The most common comorbidities were hypertension, Diabetes Mellitus followed by cardiovascular disease. Twenty-seven patients received mechanical ventilation during their admission, 13 patients were admitted to the intensive care unit, and 6 patients developed para-pneumonic effusion as a complication. In-hospital Mortality rate was 13.5%. &nbsp; &nbsp; Conclusion:&nbsp; This study supports the current literature where pneumococcal infection is more prevalent in elderly and those with comorbidities. Mortality was related to age, certain chronic medical illness, admission to intensive care unit and need for mechanical ventilation