Emerging role of SIRT2 in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the most devastating cancer types, accounting for >80% of lung cancer cases. The median relative survival time of patients with NSCLC is <1 year. Lysine acetylation is a major post-translational modification that is required for various biological processes, and abnormal protein acetylation is associated with various diseases, including NSCLC. Protein deacetylases are currently considered cancer permissive partly due to malignant cells being sensitive to deacetylase inhibition. Sirtuin 2 (SIRT2), a primarily cytosolic nicotinamide adenine dinucleotide-dependent class III protein deacetylase, has been shown to catalyze the removal of acetyl groups from a wide range of proteins, including tubulin, ribonucleotide reductase regulatory subunit M2 and glucose-6-phosphate dehydrogenase. In addition, SIRT2 is also known to possess lysine fatty deacylation activity. Physiologically, SIRT2 serves as a regulator of the cell cycle and of cellular metabolism. It has been shown to play important roles in proliferation, migration and invasion during carcinogenesis. It is notable that both oncogenic and tumor suppressive functions of SIRT2 have been described in NSCLC and other cancer types, suggesting a context-specific role of SIRT2 in cancer progression. In addition, inhibition of SIRT2 exhibits a broad anticancer effect, indicating its potential as a therapeutic for NSCLC tumors with high expression of SIRT2. However, due to the diverse molecular and genetic characteristics of NSCLC, the context-specific function of SIRT2 remains to be determined. The current review investigated the functions of SIRT2 during NSCLC progression with regard to its regulation of metabolism, stem cell-like features and autophagy.

Comparison of bone tunnel and suture anchor techniques in the modified Broström procedure for chronic lateral ankle instability.

BACKGROUND: The modified Broström procedure is frequently used to treat chronic lateral ankle instability. There are 2 common methods of the modified Broström procedure, which are the bone tunnel and suture anchor techniques. PURPOSE: To compare the clinical outcomes of the modified Broström procedure using the bone tunnel and suture anchor techniques. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Eighty-one patients (81 ankles) treated with the modified Broström procedure for chronic lateral ankle instability constituted the study cohort. The 81 ankles were divided into 2 groups, namely, a bone tunnel technique (BT group; 40 ankles) and a suture anchor technique (SA group; 41 ankles). The Karlsson score, American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, anterior talar translation, and talar tilt angle were used to evaluate clinical and radiographic outcomes. The BT group consisted of 32 men and 8 women with a mean age of 34.8 years at surgery and a mean follow-up duration of 34.2 months. The SA group consisted of 33 men and 8 women with a mean age of 33.3 years at surgery and a mean follow-up duration of 32.8 months. RESULTS: Mean Karlsson scores improved significantly from 57.0 points preoperatively to 94.9 points at final follow-up in the BT group and from 59.9 points preoperatively to 96.4 points at final follow-up in the SA group. Mean AOFAS scores also improved from 64.2 points preoperatively to 97.8 points at final follow-up in the BT group and from 70.3 points preoperatively to 97.4 points at final follow-up in the SA group. Mean anterior talar translations in the BT group and SA group improved from 9.0 mm and 9.2 mm preoperatively to 6.5 mm and 6.8 mm at final follow-up, respectively. Mean talar tilt angles were 12.0° in the BT group and 12.5° in the SA group preoperatively and 8.8° at final follow-up for both groups. No significant differences were found between the 2 groups in terms of the Karlsson score, AOFAS score, anterior talar translation, and talar tilt angle. CONCLUSION: The bone tunnel and suture anchor techniques of the modified Broström procedure showed similar good functional and radiographic outcomes. Both techniques appear to be effective and reliable methods for the treatment of chronic lateral ankle instability.

Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.

Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.

Discovery of (2E)-3-{2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an orally active histone deacetylase inhibitor with a superior preclinical profile.

A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC(50)), liver microsomal stability (t(1/2)), cytochrome P450 inhibitory (3A4 IC(50)), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.

Structure-activity relationships of bivalent aminoglycosides and evaluation of their microbiological activities.

A library of 4,5- and 4,6-linked bivalent aminoglycoside (AMG) antibiotics consisting of neamine and nebramine pharmacophores have been synthesized. We probed the effect of the linker on antibiotic activity with a series of selected synthetic analogues with varied length and substituents. A number of compounds demonstrated in vitro activity against several bacterial strains and showed activity against drug resistant strains of Pseudomonas aeruginosa. Among the compounds prepared, analogues 12a-d were novel 4,6-linked AMGs containing the nebramine pharmacophore. In addition the lead compound OPT-11 possessed an ED(50) of

Apolipoprotein D in the Niemann-Pick type C disease mouse brain: an ultrastructural immunocytochemical analysis.

Enhanced apoD gene expression and abnormally high levels of apoD protein accumulation in the brain have been previously documented as features of the neurodegenerative disorder, Niemann-Pick Type C disease (NP-C). In the present study we have used immunocytochemistry and light and electron microscopy to elucidate the cellular and subcellular distribution of apoD in the Balb/c NIH npc1(-/-) mouse brain. The normal mouse brain demonstrates low levels of apoD-expressing glia particularly in the cerebellar white matter. In contrast, abundant, strongly apoD-immunolabeled cells were observed in select grey matter nuclei, including the globus pallidus, thalamus, and substantia nigra, and in white matter tracts within the internal capsule and cerebellum of NP-C mouse brain. These brains regions have been previously shown to display the most significant neurodegenerative changes in the NP-C mouse. Ultrastructural analysis revealed dense apoD immunoreactivity on the nuclear envelopes of cells that have the morphological features of oligodendrocyte precursor-like cells and light staining on astrocytes. These results define the cellular and subcellular pattern of expression of apoD in NP-C mouse brain and suggest a possible role for this lipocalin in the pathophysiology of this disorder.

Glyco-optimization of aminoglycosides: new aminoglycosides as novel anti-infective agents.

Glyco-optimization (OPopS) of aminoglycosides has been performed by replacing the existing sugar moiety with a variety of sugar derivatives. Glycosylation of the 6-position of nebramine provided a library of novel 4,6-linked aminoglycosides (AMGs). Among them, compounds 8b,g,i,l, and 8u with 2"-amino, 2",3"-diamino, 2",4"-diamino, 3",4"-diamino, 3"-amino groups, respectively, showed significant antimicrobial activity against Gram-(+) and -(-) bacteria. Several were particularly potent against Pseudomonus aeruginosa with MICs in the 1-2 microg/mL range.