Dorzagliatin (Hua Medicine) is an oral dual-acting full glucokinase (GK) activator being developed for type 2 diabetes . More than 50 years since the first report of the role of GK in glucose metabolism, no agents targeting this enzyme have been approved, although not for lack of trying. We recently covered a partial GK activator [...]

Chugai’s PCO371 is an oral, biased agonist and "molecular wedge" of the class B GPCR, PTHR1, that first entered development for hypoparathyroidism in 2015 (NCT02475616). While Class A GPCRs, which typically have compact ligandable pockets are the most common targets for approved drugs, Class B GPCRs like PTHR1, GLP-1R, and CGRP are notoriously difficult to drug since they normally bind large peptides with long transmembrane tunnels that are not easily bound by small molecules. This article explains what makes PCO371 a big deal for GPCR drug discovery.

The recently released WHO INN proposed names list includes the structure and name of Structure Therapeutics’ oral small molecule GLP-1R agonist, aleniglipron (GSBR-1290). Seemingly emerging from a “fast-follower” program based on Chugai/Eli Lilly’s orforglipron, the compound includes an unusual phosphine oxide motif and has shown positive results on plasma glucose levels and bodyweight in a Ph. IIa study.

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.

Novartis' NLRP3 inhibitor, NVP-DFV890, features a unique sulfonimidamide motif designed to reduce hydrolysis relative to traditional sulfonylureas. This potent compound, with promising PK in humans, is advancing through multiple clinical studies, including Ph. II trials for coronary heart disease and knee osteoarthritis. Presented by Angela Mackay at the EFMC-ISMC 2024 joint conference in Rome, this overview covers NVP-DFV890's discovery, as well as its preclinical PK and PD data.