Zunsemetinib (ATI-450, CDD-450) is a p38α- MK2 complex inhibitor discovered by Confluence Technologies and developed by Confluence spinout, Aclaris Therapeutics. The molecule has a unique molecular glue-like mechanism of action that held promise in immunology, but sadly recent results have led to its discontinuation. This article reviews the target, its mechanism, and why it mattered.

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 [...]

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.

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 [...]

PRN1008 (rilzabrutinib, Sanofi) is an oral, reversible covalent Bruton’s tyrosine kinase (BTK) inhibitor in a Ph. III trial for immune thrombocytopenia. A simultaneously published inhibitor, PRN473, is in development as a topical treatment for atopic dermatitis. Following target discovery in 1993, and subsequent approval of the first [...]