Ribociclib is a potent, selective and orally bioavailable CDK4/6 inhibitor which is FDA approved as a first-line therapy for HER2- / ER+ advanced breast cancers. A target pursued by a global Novartis / Astex partnership, molecular discovery and optimization was driven by a strong structure-based understanding. However, it was a discovery that <i>might not have been </i>except for a keen awareness of cross-project data, spontaneous collaborations, and an eagerness to chase every lead.<br/>TNO155 is a first-in-class allosteric SHP2 modulator currently in Phase I cancer clinical trials. A novel approach to high-throughput screening was utilized to pinpoint an allosteric binding site with a diverse set of hit molecules. X-ray crystallography and structure-based design drove a scaffold-morphing strategy incorporating complex spirocyclics and cross-molecular modulation of physico-chemical properties leading to the highly optimized molecule.<br/>Learn the design strategies and unique chemistry that enabled the discovery of these two exciting molecules for the treatment of cancer.

Tale of two molecules: The discovery of targeted anti-cancer agents ribociclib and TNO155

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.