Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display.

Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the C-terminus. Structural modifications near the C-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries.

Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor.

Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including Clog P can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.4 × 10-6 cm/s or more in a Caco-2 permeability assay; and (v) while keeping the cyclic peptide's main-chain conformation, we found one example where the RAS protein structure was changed dramatically through induced-fit to our peptide side chain. This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski's rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits.

Pembrolizumab-induced myasthenia gravis with myositis and presumable myocarditis in a patient with bladder cancer.

INTRODUCTION: Pembrolizumab cause immune-related adverse events. We herein report a case of advanced bladder cancer, who treated with pembrolizumab and exhibited intriguing clinical course. CASE PRESENTATION: A 63-year-old man with bladder carcinoma was treated by radical cystectomy, however, the bladder carcinoma recurred and invaded to the rectum. He was treated by combination therapy using gemcitabine and cisplatin, which were not effective for the tumor. He subsequently underwent treatment with pembrolizumab. In several 30 days, he suffered from the symptoms of myasthenia gravis. Serum levels of creatine kinase, its isozyme creatine kinase-myocardial band, and troponin I were elevated. Electrocardiography showed a right bundle branch block. These findings suggested that he was myasthenia gravis with general myositis and presumable myocarditis. Oral prednisolone administration significantly attenuated these findings. The tumor drastically shrunk only by the single injection of pembrolizumab. CONCLUSION: Early intervention with corticosteroid was effective for neuromuscular complications due to pembrolizumab.

Discovery of novel benzoxazinones as potent and orally active long chain fatty acid elongase 6 inhibitors.

A series of benzoxazinones was synthesized and evaluated as novel long chain fatty acid elongase 6 (ELOVL6) inhibitors. Exploration of the SAR of the UHTS lead 1a led to the identification of (S)-1y that possesses a unique chiral quarternary center and a pyrazole ring as critical pharmacophore elements. Compound (S)-1y showed potent and selective inhibitory activity toward human ELOVL6 while displaying potent inhibitory activity toward both mouse ELOVL3 and 6 enzymes. Compound (S)-1y showed acceptable pharmacokinetic profiles after oral dosing in mice. Furthermore, (S)-1y significantly suppressed the elongation of target fatty acids in mouse liver at 30 mg/kg oral dosing.

Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists: reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect.

A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp(34)NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.

A comparative study of ethylene oxide gas, hydrogen peroxide gas plasma, and low-temperature steam formaldehyde sterilization.

OBJECTIVE: To compare the efficacies of ethylene oxide gas (EOG), hydrogen peroxide gas plasma (PLASMA), and low-temperature steam formaldehyde (LTSF) sterilization methods. METHODS: The efficacies of EOG, PLASMA, and LTSF sterilization were tested using metal and plastic plates, common medical instruments, and three process challenge devices with narrow lumens. All items were contaminated with Bacillus stearothermophilus spores or used a standard biological indicator. RESULTS: EOG and LTSF demonstrated effective killing of B. stearothermophilus spores, with or without serum, on plates, on instruments, and in process challenge devices. PLASMA failed to adequately sterilize materials on multiple trials in several experiments, including two of three plates, two of three instruments, and all process challenge devices. CONCLUSIONS: Our results suggest that PLASMA sterilization may be unsuccessful under certain conditions, particularly when used for items with complex shapes and narrow lumens. Alternatively, LTSF sterilization demonstrates excellent efficacy and is comparable to EOG sterilization. LTSF could potentially act as a substitute if EOG becomes unavailable due to environmental concerns.