“compound 12j” is a potent agonist of the ghrelin hormone receptor, activation of which stimulates growth hormone secretion and appetite among other activities. Ghrelin receptor antagonists have previously been explored to treat disorders related to obesity such as diabetes, but an agonist could be useful in treating atrophic disorders like [...]

Merck’s macrocyclic PCSK9 protein-protein interaction (PPI) inhibitor, MK-0616, is a once-daily PCSK9-lowering and LDL-cholesterol-lowering small molecule that has recently demonstrated antibody-like efficacy as an oral agent in the clinic. The program highlights numerous technical achievements at the forefront of modern drug discovery, and will set a standard for modern “classics in drug discovery” for some time.

On Mar. 14th, 2024, resmetirom (REZDIFFRA™) became the first and only medicine approved by the FDA for the treatment of NASH (non-alcoholic steatohepatitis, aka MASH). Resmetirom, an oral, liver-targeting, once-daily THR-β-selective agonist originally discovered at Roche Nutley, was first highlighted as a Molecule of the Month in Dec. 2022. Now, with the FDA’s accelerated approval, this 2023 Molecule of the Year nominee reflects a historic milestone for liver drug discovery. This article reviews how the molecule works, how it was discovered, and why it’s a big deal.

Pfizer disclosed the structure and discovery of their oral small molecule BDK inhibitor/degrader, PF-07328948, during the ACS Fall 2024 First-Time Disclosures session in Denver. The team identified a thiophene carboxylic acid-based hit targeting an allosteric pocket on BDK. Through optimization, they overcame challenges such as potential IADRs and BDK-E2 complex stabilization. By manipulating the dihedral angle of the methoxy group, they enhanced binding interactions, verifying PF-07328948's unexpected mechanism of action in vivo. PF-07328948 is currently Ph. I trials.

BI-9787 is a potent zwitterionic inhibitor of KHK (ketohexokinase) designed to explore the therapeutic potential of KHK inhibition in metabolic disorders like diabetes, non-alcoholic fatty liver disease, and NASH (non-alcoholic steatohepatitis).