Molecule Highlights
In August 2024, seladelpar (LivdelziTM) became the first FDA-approved selective agonist of PPARδ (peroxisome proliferator-activated receptor δ), following an almost 20-year journey from the original discovery and patent publications. Originally developed by CymaBay in collaboration with Johnson & Johnson, approval was granted to Gilead Sciences following their February 2024 purchase of CymaBay Therapeutics for $4.3B. Seladelpar was approved as a second-line treatment for patients with primary biliary cholangitis.
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.
RLY-2608 is an oral, mutant-selective PI3Kα allosteric inhibitor from Relay Therapeutics. Current FDA-approved PI3Kα modulator (alpelisib) and a clinically advanced molecule (inavolisib) are limited by their off-target toxicities associated with the inhibition of WT PI3Kα, leading to hyperglycemia and rash. RLY-2608 is currently in a Ph. I as a single agent and in combination with fulvestrant for HR+/HER2- breast cancer treatment. This article reviews the discovery of RLY-2608, its mechanism of mutant selectivity, how it compares to other molecules, recent clinical developments, and more.
Infection with the malaria parasite, Plasmodium falciparum, is a leading cause of fatality in the tropical regions of the world, with over 240M infections and >600k deaths each year. Currently, over half of the world population is at risk of infection and with the rise of resistance against current treatments, the need for new antimalarials is clear. At the ACS Fall 2024 conference in Denver, CO, Novartis outlined the structure and discovery story of NVP-IWY357, a novel antimalarial that has no cross-resistance to current drugs and the potential to achieve a single-dose cure.
August’s Molecules of the Month include Kannalife Sciences’ GPR55 antagonist for chemotherapy-induced neuropathic pain and Boehringer Ingelheim’s zwitterionic inhibitor of KHK for metabolic disorders. We also feature bomedemstat, Merck’s irreversible LSD1 inhibitor, which has entered a pivotal Ph. III trial. Other notable molecules from August include a small peptide inhibitor of the Fas receptor [...]
ONL1204 is ONL Therapeutics' small peptide inhibitor of the Fas receptor for IRD.
Vactosertib is an orally bioavailable TGFβ type I receptor kinase inhibitor, that has demonstrated safety, tolerability, and clinical efficacy in combination with pomalidomide in a Ph. Ib trial for RRMM.
Nerandomilast (BI 1015550) is Boehringer Ingelheim’s PDE4B inhibitor with demonstrated clinical potential in treating IPF.
Xanamem® is Actinogen Medical's cortisol-blocking drug targeting the 11β-HSD1 (11β-hydroxysteroid dehydrogenase) enzyme.
BAY-2925976 is a highly selective ARα2C (alpha-2c adrenergic receptor) antagonist with improved brain penetration and efficacy, aimed at treating OSA.
Bomedemstat (MK-3543, IMG-7289) is Merck’s irreversible LSD1 (lysine-specific demethylase 1) inhibitor for MPNs.
Compound 8 is a dual 5-HT2A and 5-HT2C receptor inverse agonist developed to address the limitations of pimavanserin.
Compound 20 is a galactose-based monosaccharide Gal-3 inhibitor from Bristol Myers Squibb that shows potential in targeting fibrotic diseases.
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).
KLS-13019 is a CBD (cannabidiol) analogue and GPR55 (G protein-coupled receptor 55) antagonist from Kannalife Sciences, which shows promise as a novel therapeutic for neuropathic pain, particularly chemotherapy-induced neuropathic pain.
This table features a selection of some of the best books on drug discovery, as well as related topics such as pharmacology, toxicology, pharmaceutics, and biotech. While nothing can replace hands-on industry experience, a few books serve as valuable references and offer insights into the realities of drug discovery. We recommend this list as a useful technical resource or as an informative introduction to the broader field of drug discovery, beyond any single discipline.
This article highlights a patent application from Monte Rosa Therapeutics that discloses the biological activity of compounds that act as VAV1 molecular glue degraders, providing a summary of key data for selected molecules disclosed in the patent application.