The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, are potent BACH1 inhibitors

Abstract

The transcription factor BACH1 is a potential target against a variety of chronic conditions linked to oxidative stress and inflammation, and formation of cancer metastasis. However, only a few BACH1 degraders/inhibitors have been described. BACH1 is a transcriptional repressor of heme oxygenase 1 (HMOX1), which is positively regulated by transcription factor NRF2 and is highly inducible by derivatives of the synthetic oleanane triterpenoid 2- cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO). Most of the therapeutic activities of these compounds are due to their anti-inflammatory and antioxidant properties, which are widely attributed to their ability to activate NRF2. However, with such a broad range of action, these drugs may have other molecular targets that have not been fully identified and could also be of importance for their therapeutic profile. Herein we identified BACH1 as a target of CDDO-derivatives, but not CDDO. While both CDDO and CDDO-derivatives activate NRF2 similarly, only CDDO-derivatives inhibit BACH1, which explains the much higher potency of CDDO-derivatives as HMOX1 inducers compared with unmodified CDDO. Notably, we demonstrate that CDDO-derivatives inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. Altogether, our study identifies CDDO-derivatives as dual KEAP1/BACH1 inhibitors, providing a rationale for further therapeutic uses of these drugs.