DescriptionKeap1-Nrf2-ARE system represents a key signaling pathway in the regulation of cellular defense mechanisms against oxidative stress and inflammation. Activation of Keap1-Nrf2-ARE system can induce the expression of a number of antioxidant defense enzymes and proteins critical for preventing oxidative damage, inflammation and tumorigenesis. Curcumin exhibits antioxidant, anti-inflammatory and anti-carcinogenic properties and is demonstrated as an indirect inhibitor of Keap1-Nrf2 protein-protein interaction. Novel classes of iminothiazinylbutadienols and divinylpyrimidinethiones were designed and synthesized as analogs of curcumin with its β-diketone moiety masked as a heterocyclic adduct with thiourea. The chemical stability of these novel heterocyclic compounds was improved as compared to curcumin. The biological activity evaluations revealed that some of these new curcumin analogs are more effective ARE activators than curcumin and isothiocyanates. Most available modulators of Keap1-Nrf2-ARE pathway modify the cysteine sulfhydryl groups of Keap1 for ARE activation. There are safety concerns about these thiol-reactive compounds. A high-throughput screen (HTS) of the MLPCN library identified the first-in-class inhibitor specifically for the direct inhibition of the Keap1-Nrf2 protein-protein interaction. The HTS hit has three chiral centers and the active stereoisomer was designated as LH601A and its stereochemistry was confirmed by X-ray crystallography and stereospecific synthesis. Various analogs of LH601A were designed and synthesized to improve the binding affinity. The obtained structure activity relationships (SAR) provided guidance for further structural optimization. Several analogs showed to be more potent than LH601A. These direct Keap1-Nrf2 inhibitors can mimic the actions of electrophiles in the induction of cytoprotective enzymes but are more selective and specific. Therefore, these direct inhibitors of Keap1-Nrf2 protein-protein interaction have great potential to be developed into innovative therapeutic agents for many diseases and conditions involving oxidative stress.