This was a loaded month for pioneering drug discovery programs! Among the highlights are a reversible-covalent inhibitor from Novartis, the hotly followed SHP2 inhibitor from Novartis, several innovative compounds from Pfizer including an oral GLP-1R agonist with a cryo-EM structure, a liver-targeted ACC inhibitor, and an oral KHK inhibitor. Remarkably, half of the molecules are negatively charged or pro-drugs of anions, and several have oral bioavailability beyond what a chemist 20 years ago would have thought probable. Most of these don’t look like they would be low-clearance, high bioavailability drugs, but they are! Detailed comments and links below.