In 2022, Amgen acquired ChemoCentryx for $4B in cash, primarily for avacopan, a first-in-class treatment approved in 2021 for a rare automimmune condition, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Scientifically, it is notable that avacopan is the first small molecule targeting the complement pathway to be [...]

Jecure’s JT001 is a selective inhibitor of NLRP3 inflammasome and among the earlier compounds in this now highly competitive space. In 2018, Genentech bought Jecure Therapeutics for an undisclosed amount, gaining access to Jecure’s NLRP3 inhibitor JT001. While there are many other NLRP3 inhibitors now in the space, JT001 is an interesting example of an initial attempt to overcome liver toxicity with well-known NLRP3 inhibitor MCC950. However, the molecule ran into its own kidney toxicity issues, making this an intriguing toxicology case study.

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 Bristol Myers Squibb (BMS) HPK1 kinase inhibitor, “compound 24” is an oral tool compound intended for cancer immunotherapy, with >50x selectivity against family members including GLK. The starting point was an IRAK4 kinase inhibitor identified from historical kinome selectivity data. A homology-model based on MST1 was used for [...]