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 [...]

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.

NT-0796 is NodThera's pro-drug inhibitor of the NLRP3 inflammasome. NT-0796 is currently in a Ph. Ib/IIa trial in obese individuals at risk of developing atherosclerotic cardiovascular diseases. NT-0796 has the potential to reduce neuroinflammation in Parkinson’s disease. The NLRP3 inflammasome has emerged as a hot target due to its connection to Alzheimer’s disease, Parkinson’s disease, gout, and other diseases. Here is a detailed review of the role of NLRP3 inhibition in treating atherosclerosis, how NT-0796 was identified, and what makes it special, clinical development, and more.

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 [...]

PF-07054894 is a potential first-in-class, oral Ph. I clinical candidate targeting the chemokine receptor CCR6 for ulcerative colitis (NCT05549323). Several companies have pursued antibodies and small molecules targeting CCR6 or its endogenous ligand, CCL20 (e.g. GSK3050002) for immunological conditions including other preclinical squaramides (e.g. Galderma, Allergan, ChemoCentryx) and other series (e.g. Takeda), but PF-07054894 appears to be the first selective CCR6 antagonist to enter clinical development.