Glutaminase (GLS), which is responsible for the conversion of glutamine to glutamate, plays a vital role in up-regulating cell metabolism for tumor cell growth and is considered to be a valuable therapeutic target for cancer treatment. Based on this important function of glutaminase in cancer, several GLS inhibitors have been developed in both academia and industry. Most importantly, Calithera Biosciences Inc. is actively developing the glutaminase inhibitor CB-839 for the treatment of various cancers, and it is currently being evaluated in phase 1 and 2 clinical trials. In this review, recent efforts to develop small molecule glutaminase inhibitors that target glutamine metabolism in both preclinical and clinical studies are discussed. In particular, more emphasis is placed on CB-839 because it is the only small molecule GLS inhibitor being studied in a clinical setting. The inhibition mechanism is also discussed based on X-ray structure studies of thiadiazole derivatives present in glutaminase inhibitor BPTES. Finally, recent medicinal chemistry efforts to develop a new class of GLS inhibitors are described in the hopes of providing useful information for the next generation of GLS inhibitors.

We report the first total synthesis of micrococcin P2 (MP2, 1) by a diversity-oriented route that incorporates a number of refinements relative to earlier syntheses. Biological data regarding the activity...

ObjectiveThe risk factors of reoperation after microdecompression (MD) for lumbar spinal stenosis (LSS) are unclear. In this study, we presented the outcomes of MD for degenerative LSS and investigated the risk factors associated with reoperation.MethodsA retrospective review was conducted using the clinical records and radiographs of patients with LSS who underwent MD. For clinical evaluation, we used the Japanese Orthopedic Association (JOA) scoring system for low back pain, body mass index, and Charlson comorbidity index. For radiological evaluation, disc height, facet angle, and sagittal rotation angle were measured in operated segments. Also the Modic change and Pfirrmann grade for degeneration in the endplate and disc were scored.ResultsForty-three patients aged 69±9 years at index surgery were followed for 48±25 months. The average preoperative JOA score was 6.9±1.6 points. The score improved to 9.1±2.1 points at the latest follow-up (p<0.001). Seven patients (16.3%) underwent reoperation. Clinical and radiological factors except operation level and Pfirrmann grade showed a p-value >0.1. Patients with Pfirrmann grade IV and lower lumbar segment had a 29.1% rate of reoperation (p=0.001), whereas patients without these factors had a 0% rate of reoperation.ConclusionModerate disk degeneration (Pfirrmann IV) in lower lumbar segments is a risk factor of disk herniation or foraminal stenosis requiring reoperation after MD in LSS.

We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERRγ but also exhibited enhanced pharmacokinetic profile compared with 3 (GSK5182). 6g and 10b had comparable potency to 3 and were far more selective for ERRγ over the ERRα, -β, and ERα. The in vivo pharmacokinetic profiles of 6g and 10b were further evaluated, as they possessed superior in vitro ADMET profiles compared to the other compounds. Additionally, we observed a significant increase of fully glycosylated NIS protein, key protein for radioiodine therapy in anaplastic thyroid cancer (ATC), in 6g- or 10b-treated CAL62 cells, which indicated that these compounds could be promising enhancers for restoring NIS protein function in ATC cells. Thus, 6g and 10b possess advantageous druglike properties and can be used to potentially treat various ERRγ-related disorders.

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