Covalent inhibitors of the RAS binding domain of PI3Kα impair tumor growth driven by RAS and HER2.

Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3K's role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block the ability of RAS to activate PI3K activity.

Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase.

WRN helicase is a promising target for treatment of cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms. Currently there are no approved drugs directly targeting human DNA or RNA helicases, in part owing to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemoproteomics-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214.

Evolution of Volatile and Phenolic Compounds during Bottle Storage of Merlot Wines Vinified Using Pulsed Electric Fields-Treated Grapes.

This study aimed to elucidate changes in volatile, phenolic, and oenological profiles of wines vinified from Pulsed Electric Fields (PEF)-treated and untreated Merlot grapes during bottle storage of up to 150, 90, and 56 days at 4 °C, 25 °C, and 45 °C, respectively, through chemometrics technique. Wines produced from untreated grapes and those PEF-treated at four different processing conditions (electric field strength 33.1 and 41.