MAPKAPK5 and Alzheimer disease: Complex-selective inhibitors were designed to addressthese issues.CDD-450 targets the composite ATP site at the p38/MK2 interface, preventingMK2 phosphorylation while sparing other p38 substrates such as ATF2and PRAK. Its SAR-guided optimizationyielded Compound 36, with improved potency and stability. However, because these inhibitors still occupythe ATP-binding cleft, they may affect other p38 functions criticalfor neuronal homeostasis. Clinically,the benefit of p38 inhibition in AD remains uncertain.