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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The US Centers for Disease Control and Prevention (CDC) lists Clostridioides difficile as an urgent bacterial threat. Yet, only two drugs, vancomycin and fidaxomicin, are approved by the FDA for the treatment of C. difficile infections as of this writing, while the global pipeline of new drugs is sparse at best. Thus, there is a clear and urgent need for new antibiotics against that organism. Herein, we disclose that AJ-024, a nitroimidazole derivative of a 26-membered thiopeptide, is a promising anti-C. difficile lead compound. Despite their unique mode of action, thiopeptides remain largely unexploited as anti-infective agents. AJ-024 combines potent in vitro activity against various strains of C. difficile with a noteworthy safety profile and desirable pharmacokinetic properties. Its time-kill kinetics against a hypervirulent C. difficile ribotype 027 and in vivo (mouse) efficacy compare favorably to vancomycin, and they define AJ-024 as a valuable platform for the development of new anti-C. difficile antibiotics.

In order to identify structural features of pyrimethamine (5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine) that contribute to its inhibitory activity (IC50 value) and chaperoning efficacy toward β-N-acetylhexosaminidase, derivatives of the compound were synthesized that differ at the positions bearing the amino, ethyl, and chloro groups. Whereas the amino groups proved to be critical to its inhibitory activity, a variety of substitutions at the chloro position only increased its IC50 by 2-3-fold. Replacing the ethyl group at the 6-position with butyl or methyl groups increased IC50 more than 10-fold. Surprisingly, despite its higher IC50, a derivative lacking the chlorine atom in the para-position was found to enhance enzyme activity in live patient cells a further 25% at concentrations >100 μM, while showing less toxicity. These findings demonstrate the importance of the phenyl group in modulating the chaperoning efficacy and toxicity profile of the derivatives.

Clostridioides dif ficile infection is a global public health threat. Extensive in vitro assays using clinical isolates have identified micrococcin P2 (MP2, 1) as a particularly effective anti-C. diff icile agent. MP2 possesses a mode of action that differs from other antibiotics and pharmacokinetic properties that render it especially promising. Its time−kill studies have been investigated using hypervirulent C. dif f icile ribotype 027. DSS (dextran sulfate sodium)-induced in vivo mouse studies with that strain indicate that 1 is better than vancomycin and fidaxomicin. Thus, micrococcin P2 is a valuable platform to be exploited for the development of new anti-C. dif f icile antibiotics.Clostridioides dif f icile is a Gram-positive, spore-forming, toxinproducing, anaerobic bacteria that is becoming a serious health threat. 1 The organism causes severe diarrhea with lifethreatening complications, 2 such as toxic megacolon, pseudomembranous colitis, and systemic inflammatory response syndrome. 3 The prevalence of the hypervirulent strain of C. diff icile PCR ribotype 027 4 adds additional clinical concerns due to its severe disease presentation. C. dif ficile is thus designated as an urgent threat by the U.S. Centers for Disease Control and Prevention (CDC). 5 In the U.S. alone, more than 220 000 cases of C. diff icile infection (CDI), with 12 800 deaths, were reported in 2019. In South Korea, the estimated CDI rate is as high as in the U.S., but the lack of national-level support for antimicrobial stewardship undermines public awareness. 6 Currently, only two antibiotics, vancomycin and fidaxomicin, are approved by the FDA for the treatment of CDI. 7 However, vancomycin suffers from high rates of relapse (25% to 30%), 8 and its broad antibiotic spectrum against Gram-positive bacteria leads to an undesirable reduction in microbiome diversity. 9 Fidaxomicin has lower recurrence rates because of its better selectivity toward C. dif f icile, but its high price limits its usage. On the other hand, vancomycin is an antibiotic of last resort against a number of deadly human pathogens, and its use must be limited in order to prevent the development of resistance. 10 In the latter respect, the emergence of bacteria that are resistant to all currently available antibiotics is a health threat of great concern. 11 It is estimated that antimicrobial resistance (AMR) will cause 700 000 deaths per year by 2050, if no immediate action is taken. 12 The financial burden of such illnesses is anticipated to be significant. Clearly, the development of new antibiotics is an urgent need. 13