Synthesis of MDM2-p53 Inhibitor BI-0282 via a Dipolar Cycloaddition and Late-Stage Davis-Beirut Reaction.

Herein, we report the structure and synthesis of the potent MDM2-p53 inhibitor BI-0282. The complex spirooxindole scaffold bearing four stereocenters embedded in a rigid polycyclic ring-system was effectively prepared on a multi-gram scale in only five synthesis steps employing a three-component 1,3-dipolar cycloaddition and a late-stage Davis-Beirut reaction as key steps.

Getting a Grip on the Undrugged: Targeting β-Catenin with Fragment-Based Methods.

Aberrant WNT pathway activation, leading to nuclear accumulation of β-catenin, is a key oncogenic driver event. Mutations in the tumor suppressor gene APC lead to impaired proteasomal degradation of β-catenin and subsequent nuclear translocation. Restoring cellular degradation of β-catenin represents a potential therapeutic strategy.