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.

In the Eye of the Beholder: A Stakeholder Analysis of the Value of the "Promotion in Place" Competency-Based Time-Variable Graduate Medical Education Pilot.

Purpose: Competency-based time-variable (CBTV) graduate medical education (GME) has been implemented in Canada, Europe, and the United States, yet its perceived value has not been explored. Promotion in Place (PIP) is a CBTV GME program in which residents graduating early advance to attending status with "sheltered independence" until the standard graduation date. This study describes perceived value of CBTV GME and PIP at Mass General Brigham by capturing diverse stakeholder perspectives.

Prodrug Strategy to Address Impaired Oral Absorption of a Weakly Basic TYK2 Inhibitor Caused by a Gastric Acid-Reducing Agent.

The pH-dependent solubility of the weakly basic TYK2 inhibitor posed a risk to its advancement, given that drugs with such profiles have exhibited drug-drug interaction (DDI) with stomach acid-reducing agents in humans. In a rat model of pH dependence, preadministration of famotidine caused a 2.4-fold lower exposure of when compared to control rats, implying that pH-dependent oral absorption can reduce the active drug's exposure and translate to subtherapeutic treatment.

Validation of high-sensitivity assays to quantitate cerebrospinal fluid and serum β-galactosidase activity in patients with GM1-gangliosidosis.

GM1-gangliosidosis (GM1) is a lysosomal storage disorder caused by mutations in the galactosidase beta 1 gene () that leads to reduced β-galactosidase (β-gal) activity. This enzyme deficiency results in neuronal degeneration, developmental delay, and early death. A sensitive assay for the measurement of β-gal enzyme activity is required for the development of disease-modifying therapies.