A practical drug discovery project at the undergraduate level

A practical drug discovery project for third-year undergraduates is described. No previous knowledge of medicinal chemistry is assumed. Initial lecture-workshops cover the basic principles; then students are asked to improve the profile of a weakly potent, poorly soluble PI3K inhibitor (1). Compound array design, molecular modelling and screening data analysis are followed by laboratory work in which each student, as part of a team, attempts to synthesise at least two target compounds. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. Forty-eight target compounds have been prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and 10-fold, respectively

QSPR Studies on Aqueous Solubilities of Drug-Like Compounds

A rapidly growing area of modern pharmaceutical research is the prediction of aqueous solubility of drug-sized compounds from their molecular structures. There exist many different reasons for considering this physico-chemical property as a key parameter: the design of novel entities with adequate aqueous solubility brings many advantages to preclinical and clinical research and development, allowing improvement of the Absorption, Distribution, Metabolization, and Elimination/Toxicity profile and “screenability” of drug candidates in High Throughput Screening techniques. This work compiles recent QSPR linear models established by our research group devoted to the quantification of aqueous solubilities and their comparison to previous research on the topic

Aurora A–Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy

Although Aurora A, B, and C kinases share high sequence similarity, especially within the kinase domain, they function distinctly in cell-cycle progression. Aurora A depletion primarily leads to mitotic spindle formation defects and consequently prometaphase arrest, whereas Aurora B/C inactivation primarily induces polyploidy from cytokinesis failure. Aurora B/C inactivation phenotypes are also epistatic to those of Aurora A, such that the concomitant inactivation of Aurora A and B, or all Aurora isoforms by nonisoform–selective Aurora inhibitors, demonstrates the Aurora B/C-dominant cytokinesis failure and polyploidy phenotypes. Several Aurora inhibitors are in clinical trials for T/B-cell lymphoma, multiple myeloma, leukemia, lung, and breast cancers. Here, we describe an Aurora A–selective inhibitor, LY3295668, which potently inhibits Aurora autophosphorylation and its kinase activity in vitro and in vivo, persistently arrests cancer cells in mitosis, and induces more profound apoptosis than Aurora B or Aurora A/B dual inhibitors without Aurora B inhibition–associated cytokinesis failure and aneuploidy. LY3295668 inhibits the growth of a broad panel of cancer cell lines, including small-cell lung and breast cancer cells. It demonstrates significant efficacy in small-cell lung cancer xenograft and patient-derived tumor preclinical models as a single agent and in combination with standard-of-care agents. LY3295668, as a highly Aurora A–selective inhibitor, may represent a preferred approach to the current pan-Aurora inhibitors as a cancer therapeutic agent

ROCK2 and MYLK variants and high-altitude pulmonary edema

Gaurav Sikri, Srinivasa Bhattachar Department of Physiology, Armed Forces Medical College, Pune, Maharashtra, IndiaWe have read the article titled “ROCK2 and MYLK variants under hypobaric hypoxic environment of high altitude associate with high altitude pulmonary edema and adaptation” by Pandey et al1 with profound interest. View the original paper by Pandey and colleagues

Management of HAPE with bed rest and supplemental oxygen in hospital setting at high altitude (11,500 ft): A review of 43 cases

Objectives: To evaluate the safety and efficacy of treating high-altitude pulmonary edema (HAPE) by bed rest and supplemental oxygen in hospital setting at high altitude. Materials and Methods: In a prospective case series, all patients who were diagnosed clinically with HAPE on admission to our hospital located at a height of 11,500 ft were evaluated and managed with bed rest and oxygen supplementation. Results: A total of 43 patients of HAPE with mean age of 31 years (range 20–48 years) were admitted to our hospital. Infections followed by unaccustomed physical exertion were the predominant risk factors. 95.35% of the patients improved successfully with oxygen and bed rest alone with mean hospital stay of 2.67 ± 1.06 (1–6 days). Two patients (4.65%) required nifedipine and evacuation to lower altitude. Of this, one patient suffering from concomitant viral infection expired 4 days after evacuation to near sea level. Conclusion: Majority of the patients with HAPE where medical facilities are available can be safely treated with bed rest and oxygen supplementation at moderate high altitude without descent