Kymera's KT-474 is the first oral degrader to demonstrate activity in clinical trials outside cancer and Sanofi recently started a Ph. II trial with the molecule in AD, restoring life to IRAK4 as an immunology target. This article highlights why Kymera’s KT-474 program is scientifically notable, including how it differentiates from small molecule inhibitors, potential competitiveness with biologics, the first reported cryo-EM ternary complex of a heterobifunctional degrader, and why this 2023 Molecule of the Year Nominee will likely be considered a “landmark in drug discovery” for some time.

Zilucoplan is a macrocyclic peptide-containing drug with 15 amino acids in total, targeting the challenging-to-drug C5 complement protein and formulated for self-administered once-daily SC injection. In Sept. 2023, zilucoplan received its first global approval in Japan, followed in Oct. 2023 by FDA approval for gMG patients who are AChR antibody-positive, making zilucoplan the first drug derived from mRNA display for cyclic peptides to be approved. This case study discusses how zilucoplan was discovered and why it’s an important scientific milestone for the industry.

The Celgene/BMS PKCθ kinase inhibitor, CC-90005 , highlighted by Julien Lefranc , is a clinical candidate in Ph. I for psoriasis, with some dosing being conducted in healthy volunteers. The safety profile is impressive given how fraught with selectivity issues previous PKC inhibitors have been. The molecule is >550-fold selective for PKCθ [...]

Cerevance’s CVN293 is an oral, CNS-penetrant, selective inhibitor of potassium efflux-mediated NLRP3-inflammasome activation in microglia for the treatment of neurodegenerative disorders. Cerevance’s NETSseq platform was used to discover a microglia-specific potassium efflux channel, KCNK13, which allows modulation of the NLRP3-inflammasome in the CNS without affecting peripheral innate immunity. Read the full article to discover highlights on the CNS-penetration of highly polar compounds and how particle size can be key to oral bioavailability

GDC-2394 (Genentech) is an oral NLRP3 inflammasome inhibitor. The NLRP3 inflammasome is the best studied and most characterized inflammasome , with the protein playing a key role in the detection of inflammatory danger signals which are a hallmark of many inflammatory diseases. Hyperactivation of the NLRP3 has been implicated in the [...]