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.

A Screen of Autophagy Compounds Implicates the Proteasome in Mammalian Aminoglycoside-Induced Hair Cell Damage.

Autophagy is a degradative pathway to safely break down and recycle dysfunctional cellular components. There is prior evidence of autophagy participation during hair cell (HC) damage. Our goal was to screen compounds targeting different aspects of autophagy for their effects on HC loss due to an ototoxic aminoglycoside, gentamicin (GM).