Fragment-Based Anti-inflammatory Agent Design and Target Identification: Discovery of AF-45 as an IRAK4 Inhibitor to Treat Ulcerative Colitis and Acute Lung Injury

UC
and ALI are inflammatory diseases with limited treatment
in
the clinic. Herein, fragment-based anti-inflammatory agent designs
were carried out deriving from cyclohexylamine/cyclobutylamine and
several fragments from anti-inflammatory agents in our lab. AF-45
(IC50 = 0.53/0.60 μM on IL-6/TNF-α in THP-1
macrophages) was identified as the optimal molecule using ELISA and
MTT assays from the 33 synthesized compounds. Through mechanistic
studies and a systematic target search process, AF-45 was found to
block the NF-κB/MAPK pathway and target IRAK4, a promising target
for inflammation and autoimmune diseases. The selectivity of AF-45
targeting IRAK4 was validated by comparing its effects on other kinase/nonkinase
proteins. In vivo, AF-45 exhibited a good therapeutic
effect on UC and ALI, and favorable PK proprieties. Since there are
currently no clinical or preclinical trials for IRAK4 inhibitors to
treat UC and ALI, AF-45 provides a new lead compound or candidate
targeting IRAK4 for the treatment of these diseases.