Chiesi Farmaceutici’s CHF-6523 is an inhaled, lung-restricted, selective PI3Kδ inhibitor designed to provide relief to patients with COPD. Its development involved optimization of permeability and solubility as well as identification of a solid form amenable for dry powder inhalation. Disclosed at the EFMC-ISMC 2024 joint conference in Rome, Italy, this article covers the structure, development, and early clinical data of CHF-6523, which ultimately indicates that PI3Kδ inhibition may not provide clinical effect in reduction of lung inflammation.

Sovleplenib (HMPL-523) is an orally bioavailable Syk inhibitor being developed by HUTCHMED and is currently in Ph. II and Ph. III clinical trials for several autoimmune diseases. Derived from an HTS hit and SAR optimization, the discovery story of sovleplenib serves as an excellent case study on how to design a next-generation Syk inhibitor devoid of off-target kinase activity, mitigated hERG activity, 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.

Vorasidenib (AG-881) is a brain-penetrant allosteric inhibitor of mutant isocitrate dehydrogenases 1 and 2 (mIDH1/2) from Agios and Celgene that made headlines summer 2023 due to its stunning efficacy for treatment of glioma in patients with mIDH1/2. This Featured Case Study reviews how it was discovered, how it works, and why it matters.

Nuvalent’s lead compound, NVL-520, is an oral, brain-penetrant, TRK-sparing, and potential best-in-class ROS1 kinase inhibitor that recently entered Ph. II of the ARROS-1 trial (NCT05118789) in patients with advanced ROS1-positive NSCLC. This article highlights what makes the Nuvalent’s NVL-520 program scientifically notable, including what gives it a potential best-in-class profile as a ROS1 inhibitor, the emerging toxicology of hard-to-avoid off-targets, an interesting synthetic route to the small macrocycle, and more.