SD-208, a novel protein kinase D inhibitor, blocks prostate cancer cell proliferation and tumor Growth in Vivo by inducing G2/M cell cycle arrest

Protein kinase D (PKD) has been implicated in many aspects of tumorigenesis and progression, and is an emerging molecular target for the development of anticancer therapy. Despite recent advancement in the development of potent and selective PKD small molecule inhibitors, the availability of in vivo active PKD inhibitors remains sparse. In this study, we describe the discovery of a novel PKD small molecule inhibitor, SD-208, from a targeted kinase inhibitor library screen, and the synthesis of a series of analogs to probe the structure-activity relationship (SAR) vs. PKD1. SD-208 displayed a narrow SAR profile, was an ATP-competitive pan-PKD inhibitor with low nanomolar potency and was cell active. Targeted inhibition of PKD by SD-208 resulted in potent inhibition of cell proliferation, an effect that could be reversed by overexpressed PKD1 or PKD3. SD-208 also blocked prostate cancer cell survival and invasion, and arrested cells in the G2/M phase of the cell cycle. Mechanistically, SD-208-induced G2/M arrest was accompanied by an increase in levels of p21 in DU145 and PC3 cells as well as elevated phosphorylation of Cdc2 and Cdc25C in DU145 cells. Most importantly, SD-208 given orally for 24 days significantly abrogated the growth of PC3 subcutaneous tumor xenografts in nude mice, which was accompanied by reduced proliferation and increased apoptosis and decreased expression of PKD biomarkers including survivin and Bcl-xL. Our study has identified SD-208 as a novel efficacious PKD small molecule inhibitor, demonstrating the therapeutic potential of targeted inhibition of PKD for prostate cancer treatment

Mitochondrial uncoupler SHC517 reverses obesity in mice without affecting food intake.

AimsMitochondrial uncouplers decrease caloric efficiency and have potential therapeutic benefits for the treatment of obesity and related metabolic disorders. Herein we investigate the metabolic and physiologic effects of a recently identified small molecule mitochondrial uncoupler named SHC517 in a mouse model of diet-induced obesity.MethodsSHC517 was administered as an admixture in food. The effect of SHC517 on in vivo energy expenditure and respiratory quotient was determined by indirect calorimetry. A dose-finding obesity prevention study was performed by starting SHC517 treatment concomitant with high fat diet for a period of 12 days. An obesity reversal study was performed by feeding mice western diet for 4 weeks prior to SHC517 treatment for 7 weeks. Biochemical assays were used to determine changes in glucose, insulin, triglycerides, and cholesterol. SHC517 concentrations were determined by mass spectrometry.ResultsSHC517 increased lipid oxidation without affecting body temperature. SHC517 prevented diet-induced obesity when administered at 0.05% and 0.1% w/w in high fat diet and reversed established obesity when tested at the 0.05% dose. In the obesity reversal model, SHC517 restored adiposity to levels similar to chow-fed control mice without affecting food intake or lean body mass. SHC517 improved glucose tolerance and fasting glucose levels when administered in both the obesity prevention and obesity reversal modes.ConclusionsSHC517 is a mitochondrial uncoupler with potent anti-obesity and insulin sensitizing effects in mice. SHC517 reversed obesity without altering food intake or compromising lean mass, effects that are highly sought-after in anti-obesity therapeutics

Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice

Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake

Global vitamin D status and determinants of hypovitaminosis D

The aim of the study was to compare the structural and functional parameters of the myocardium in different genotypes of polymorphic markers BsmI (B/b) (rs1544410) and FokI (F/f) (rs2228570) of the vitamin D receptor gene (VDR) in individuals with cardiovascular diseases (CVD). Materials and Methods. We examined 198 patients with CVD. BsmI and FokI of the VDR gene were determined by the polymerase chain reaction. The blood levels of parathyroid hormone, 25(OH)D total, endothelin-1, plasma renin activity were revealed by the method of enzyme immunoassay. The calcium and phosphorus level in the blood was defined by the colorimetric method. Echocardiography was performed by GE Logic P5 Premium (Korea) with a phased sector sensor with a frequency of 2–4 MHz in the modes M-, B-, PW, CW. Results. All participants were divided into groups according to genotypes of FokI and BsmI of the VDR gene. For each polymorphism, the groups were comparable in age, CVD, blood pressure, heart rate, body mass index and levels of the estimated biomarkers. Significant differences (p < 0.05) in the sizes of the aorta and the left atrium (LA), in the sizes and volumes of the left ventricle (LV) and its walls, the diameter of the LV outlet tract and the ejection fraction between the groups with the genotypes of FF and ff were established. In addition, differences (p < 0.05) were found in the aorta size, LA and interventricular septum between the groups with the genotypes of ff and Ff. According to the genotypes of BsmI of the VDR gene, the groups did not differ significantly in the estimated structural and functional parameters of the myocardium and aorta. Hypertrophy of the LV is diagnosed in 78.6 % of participants. Conclusions. Polymorphism of FokI, but not of BsmI of the VDR gene is associated with structural and functional parameters of the myocardium and aorta in individuals with CVD in the Grodno region of Belarus. With the greatest frequency, LV hypertrophy occurs with Ff (37.9 %) and Bb (33.8 %).Цель исследования – сравнение структурно-функциональных показателей миокарда при разных генотипах полиморфных маркеров BsmI (B/b) (rs1544410) и FokI (F/f) (rs2228570) гена рецептора витамина D (VDR) у лиц с сердечно-сосудистыми заболеваниями (ССЗ). Материалы и методы. Обследовано 198 пациентов с ССЗ. Определение BsmI и FokI гена VDR проводили методом полимеразной цепной реакции. Содержание в крови паратиреоидного гормона, 25(OH)D общего, эндотелина-1, активность ренина плазмы определяли методом иммунофер- ментного анализа. Определение в крови уровня кальция и фосфора проводилось колориметрическим методом. Эхо- кардиография выполнялась аппаратом GE Logic P5 Premium (Корея) фазированным секторным датчиком с частотой 2–4 мГц в режимах М-, В-, PW, CW. Результаты. Все обследованные были разделены на группы по генотипам FokI и BsmI гена VDR. При каждом полиморфизме группы были сопоставимы по возрасту, ССЗ, значениям артериального давления, частоте сердечных сокращений, индексу массы тела и уровням оцененных биомаркеров. Установлены достоверные (p < 0,05) отличия по размерам отделов аорты, левого предсердия (ЛП), размерам и объемам левого желудочка (ЛЖ) и его стенок, диаметром выходного тракта ЛЖ и фракцией выброса между группами с генотипом FF и ff. Кроме того, установлены отличия (p < 0,05) по размерам отделов аорты, ЛП и толщиной межжелудочковой перегородки между группами с генотипом ff и Ff. По генотипам BsmI гена VDR группы достоверно не отличались по оцененным структурно-функциональным показателям миокарда и аорты. Гипертрофия ЛЖ диагностирована у 78,6 % обследованных. Заключение. Полиморфизм FokI, но не BsmI гена VDR ассоциирован со структурно-функциональными показателями миокарда и аорты у лиц с ССЗ у жителей Гродненского региона Беларуси. С наибольшей частотой гипертрофия ЛЖ встречается при Ff (37,9 %) и Bb (33,8 %) генотипах.