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Bioorg Med Chem Lett
; 29(23): 126743, 2019 12 01.
Artículo
en Inglés
| MEDLINE
| ID: mdl-31678006
RESUMEN
We describe a series of potent and highly selective small-molecule MALT1 inhibitors, optimized from a High-Throughput Screening hit. Advanced analogues such as compound 40 show high potency (IC50: 0.01⯵M) in a biochemical assay measuring MALT1 enzymatic activity, as well as in cellular assays: Jurkat T cell activation (0.05⯵M) and IL6/10 secretion (IC50: 0.10/0.06⯵M) in the TMD8 B-cell lymphoma line. Compound 40 also inhibited cleavage of the MALT1 substrate RelB (IC50: 0.10⯵M). Mechanistic enzymology results suggest that these compounds bind to the known allosteric site of the protease.