ML385

**ML385** is a small molecule inhibitor that selectively targets and inhibits the transcription factor nuclear factor erythroid 2-related factor 2 (**NRF2**, also known as NFE2L2), which is a master regulator of cellular antioxidant defense mechanisms. ML385 binds to the Neh1 (Cap 'N' Collar Basic Leucine Zipper) domain of NRF2 and interferes with the binding of the NRF2–MAFG protein complex to regulatory DNA binding sequences. This inhibition results in decreased NRF2-mediated transcription of downstream target genes involved in antioxidant response, glutathione metabolism, and cellular detoxification. ML385 shows particular cytotoxicity and anti-tumor activity in non-small cell lung cancer (NSCLC) cells that harbor KEAP1 loss-of-function mutations or NRF2 gain-of-function mutations, which lead to constitutive NRF2 activation and therapeutic resistance[1][3][7][9]. The compound also demonstrates the ability to enhance the anti-tumor efficacy of chemotherapeutic agents such as carboplatin, paclitaxel, doxorubicin, and celastrol by decreasing NRF2-driven drug resistance pathways[1][5]. Preclinical studies have additionally indicated potential utility in other cancers with aberrant NRF2 activation, including acute myeloid leukemia (AML) and lung squamous cell carcinoma (LUSC), by promoting cell death (including ferroptosis) and suppressing PI3K‐mTOR signaling, which is partly mediated by downregulation of RagD protein expression[2][3][10]. ML385 is mainly used as a chemical probe in research laboratories for elucidating the role of NRF2 in cancer biology, chemoresistance, and as a tool compound to validate NRF2 as a therapeutic target[1][3].

Other names

ML-385ML385ML 385