Genentech announced that fenebrutinib (GDC-0853), a non-covalent BTK inhibitor entering Ph. III, showed significant human CNS exposure and reduced new brain lesions in Ph. II for relapsing multiple sclerosis. Fenebrutinib is the only reversible BTK inhibitor in Ph. III for MS, and has the opportunity to differentiate on safety relative to covalent inhibitors. This case study highlights notable challenges overcome in the discovery of fenebrutinib including surprising metabolism, animal-specific on-target toxicity, and more.

Orforglipron is an oral non-peptide glucagon-like peptide-1 (GLP-1) receptor partial agonist that entered Ph. III for obesity and type-2-diabetes mellitus (T2DM). This 2020 and 2023 Molecule of the Year nominee (nominated initially back when it was still in Ph. I) was first discovered by Chugai Pharmaceuticals under the name OWL833, then licensed by Eli Lilly for worldwide development under the name LY3502970. The article discusses where it sits in the GLP-1R agonist landscape, why it’s scientifically notable, how it works with illustrations from cryo-EM structures, its synthesis, and more.

PLX-4545 is an oral CRBN-based molecular glue degrader of IKZF2 in Ph. I trials. It potentially addresses anti-tumor immunity suppression within the TME, critical in checkpoint blocker resistance. Tumors use IKZF2 to regulate the function of regulatory T cells and inhibit effector T cells. IKZF2 depletion in regulatory T cells enhances the anti-tumor response. The discovery and structural data of PLX-4545 were presented by Kevin Freeman-Cook at the ACS Fall 2024 First-Time Disclosures session in Denver, CO. We are reporting the discovery story and its potential impact on immuno-oncology.

Arvinas’ ARV-393 is an orally bioavailable PROTAC that degrades BCL6 via CRBN-mediated ubiquitination and proteasomal degradation intended for the treatment of NHL. At the AACR San Diego 2024 meeting, Arvinas disclosed the structure and discovery story of this molecule, which exhibits first-in-class potential. This article covers the key SAR observations that led to the invention of this orally bioavailable PROTAC®, its performance in a triple-hit, high-grade BCL and R-CHOP-resistant cell line, and why sustaining BCL6 knockdown beyond 24 hours was critical for the success of this program.

Xanamem® is Actinogen Medical's cortisol-blocking drug targeting the 11β-HSD1 (11β-hydroxysteroid dehydrogenase) enzyme.