The
transcription factor BACH1 is a potential therapeutic target for a variety of
chronic conditions linked to oxidative stress and
inflammation, as well as
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 compounds 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 two
CDDO-derivatives (
CDDO-Me and
CDDO-TFEA), but not of
CDDO. While both
CDDO and
CDDO-derivatives activate NRF2 similarly, only
CDDO-Me and
CDDO-TFEA inhibit BACH1, which explains the much higher potency of these
CDDO-derivatives as HMOX1 inducers compared with unmodified
CDDO. Notably, we demonstrate that
CDDO-Me and
CDDO-TFEA inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. In an in vitro model, both
CDDO-derivatives impaired
lung cancer cell invasion in a BACH1-dependent and NRF2-independent manner, while
CDDO was inactive. Altogether, our study identifies
CDDO-Me and
CDDO-TFEA as dual KEAP1/BACH1 inhibitors, providing a rationale for further
therapeutic uses of these drugs.