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

Role of Physiological Intestinal Water in Oral Absorption

Water volume has impact when the compound has low aqueous solubility. For example, the absorption of compounds with a Biopharmaceutics Classification System class 2 or 4 is likely to be solubility-limited. Provided the formulation does not contribute to a dissolution-limited condition (e.g., particle size, Waterman and Sutton, J Control Release 86:293–304, 2003) and permeability is rapid, any impact on solubility factors in the gastrointestinal (GI) tract will directly impact the fraction absorbed These factors are in situ solubility, precipitation, and volume of water. Using GastroPlus™, models were developed with literature values of water volume in the small (SIWV) and large (LIWV) intestines for several solubility limited compounds. One or more models were developed for the mean plasma concentration-time profile of each compound. The consistency of the models with known literature and experimental data for the compounds’ solubility and precipitation was determined. The SIWV associated with best fits of solubility limited compounds averaged about 130 ml, with a range of 10–150 ml in the fasted state. The average LIWV in the fasted state was about 10 ml and ranged as large as 125 ml. The wide range of individual LIWV values is likely due to variability in pharmacokinetics, permeability, GI transit, and the observation that data set was collected during a “snapshot in time”. The preferred values of 10% organ volume for small intestine and 1–10% organ volume for large intestine are recommended in lieu of the GastroPlus default values of 40% and 10%, respectively