Potential of natural triterpenoid structures as a framework for design and development of perspective synthetic NRF2-modulating therapeutic agents

Since the discovery of NRF2, natural compounds like triterpene derivatives, taraxasterol, astragaloside, ursolic acid, and withaferin have been extensively studied, particularly because they were found to activate the NRF2 pathway as potent steroidal electrophiles [1]. These compounds are attracted to KEAP1, a nucleophilic protein, and by facilitating structural changes in KEAP1, lead to alterations in its shape and activation of NRF2.
Conversely, brusatol, a natural triterpene lactone, acts as an NRF2 inhibitor, suggesting its potential for sensitizing cancer cells, enhancing the effectiveness of cisplatin in a NRF2 dependent manner [2]. Its chemical structure served for further development of other semi-synthetic, halofuginone, that reduced NRF2 proteins level and induced selective cytotoxicity for NRF2 addicted cancer cell lines.
Oleanolic acid, a modest anti-inflammatory agent has been used as a basic structure for derivatization and obtaining of synthetic oleanane triterpenoids. Through a few modifications and addition of Michaelis acceptors in the steroid rings bardoxolone (CDDO) was revealed as a potent NRF2 activator. Pre-clinical and clinical trials confirmed the ability to activate NRF2 pathway and act as anti-inflammatory, antineoplastic and reducing chemoresistance effects [1]. Another oleanone derivative, omaveloxolone, sparked interest in natural products with triterpene structures, following its FDA approval for Friedreich’s ataxia treatment, last year [3].
Based on current research, natural triterpene compounds show significant potential for further development and optimization of semi-synthetic and synthetic therapeutic agents, offering a promising approach to targeting the NRF2 pathway.