In recent years the nuclear transcription factor (erythroid-derived 2)¿like 2 (Nrf2) has been identified as the key factor in the cell auto-protection mechanisms. Under no pathological conditions, Nrf2 is mainly located in the cytosol, bound to the Kelch like ECH associated protein 1 (Keap1). In contrast, under oxidative conditions, Keap1 changes its conformation and breaks the binding with Nrf2 allowing its accumulation and translocation to the nucleus where it induces the transcription of key antioxidant enzymes. Nrf2 dysregulation is involved in different pathologies such as cancer, cardiovascular diseases or neurodegenerative diseases, among others [1]. In recent years, a great amount of new molecules able to disrupt the interaction between Nrf2 and Keap1, have been studied, however most of them are electrophilic molecules and are prone to interact with several non-desired targets. In our group we are applying the surface plasmon resonance (SPR) technique for the identification of new non-electrophilic inhibitors of the Nrf2 - Keap1 protein-protein interaction (PPI). This kind of molecules could exhibit a more specific mechanism for the induction of Nrf2 activity. Thus, the ability of several molecules from our library to interact with the purified Kelch domain of Keap1 attached to a CM5 sensor chip has been evaluated in a SPR assay [2]. With this technique, a new hit with affinity for Keap1 was identified. The affinity value was comparable to that of the positive control ML-334, a well-known inhibitor of the Nrf2 - Keap1 PPI. Starting from this new hit, a larger family with improved potency have been obtained [3]. This new family of bis-heterocyclic compounds do not present any electrophilic character, are able to reach the central nervous system and exhibit other complementary activities such as radical scavenging and neurogenic properties, which make them potential candidates for the treatment of neurodegenerative diseases such as Alzheimer¿s disease.

Dirección General de Investigación e Innovación de la Comunidad de Madrid y Fondo Europeo de Desarrollo Regional (B2017/BMD-3827, NRD24AD-CM); Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación y FEDER (SAF2015-64948-C2-1-R, RTI2018-093955-B-C21