Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS.

Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant therapeutic targets. One approach for modulating RAS signaling is to target proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report hit-to-lead studies on quinazoline-containing compounds that bind to SOS1 and activate nucleotide exchange on RAS. Using structure-based design, we refined the substituents attached to the quinazoline nucleus and built in additional interactions not present in the initial HTS hit. Optimized compounds activate nucleotide exchange at single-digit micromolar concentrations in vitro. In HeLa cells, these quinazolines increase the levels of RAS-GTP and cause signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway

Component alignment in simultaneous bilateral or unilateral total knee arthroplasty

A bilateral total knee prosthesis procedure can be performed simultaneously in patients with bilateral gonarthrosis. The purpose of this study was to evaluate the differences in component alignment between the simultaneous bilateral TKA and unilateral TKA. A total of 20 patients out of 40 underwent simultaneous bilateral TKA, whereas 20 patients had unilateral TKA. The component alignments were compared radiographically. There was no statistically significant difference in the component alignment between the simultaneous bilateral TKA group and the unilateral TKA group. In conclusion, component alignment of the patients with simultaneous bilateral TKA is similar to that of unilateral TKA