APX3330

Studies related to the redox activity of APEX1 have shown that the combination of the redox inhibitor E3330 with 5-aminosalicylic acid (5-ASA) can effectively alleviate colitis, indicating that APEX1 has promising prospects for clinical treatment of IBD. APEX1 is required for interactions between neutrophil and intestinal epithelial cells. This study provided a mechanism demonstrating that APEX1 protein triggered the risk of UC by promoting neutrophil infiltration and compromising intestinal epithelial barrier function.

To characterize the effects of Ref-1 inhibition in vivo, global proteomics was used following treatment with the top four analogs. This study identified and characterized more potent inhibitors of Ref-1 redox function (that outperformed APX3330 by 5-10-fold) with PK studies demonstrating efficacious doses for translation to clinic.

The data suggest that APE1 is a pivotal player in ALI, closely linked to its regulation of Nrf2. Strategies involving APE1 activation to modulate Nrf2, thereby inhibiting hepatocyte ferroptosis and promoting autophagy, may represent innovative therapeutic approaches for ALI. Additionally, tert-butylhydroquinone (TBHQ) holds significant promise in the treatment of acute liver injury.

Reflux conditions promote EMT via APE1 redox-dependent E-cadherin cleavage. APE1-redox function inhibitors can have a therapeutic role in EAC.

Our findings established a novel function of APE1 in EAC progression elucidating druggable molecular vulnerabilities via targeting APE1 or YAP1 for the treatment of EAC.

We demonstrated that RelA deficient cells are more resistant to Ref-1 redox inhibitors APX3330, APX2009, and APX2014, and their sensitivity is restored in the RelA proficient cells...Further imbalancing of the redox signaling through disruption of the PRDX1-Ref-1 interaction may have therapeutic implications. Our data further support a pivotal role of RelA in mediating Ref-1 redox signaling in PDAC cells with the Kras genotype and provide novel therapeutic strategies to combat PDAC drug resistance.

Ref-1 redox inhibitor, APX3330 that completed Phase I clinical trial (NCT03375086), potently inhibited in vitro growth of a panel of MPNST cells...Two new xenolines were established from patient PDXs and are being validated for growth inhibition and downregulation of MPNST survival genes with Ref-1 knockdown and redox inhibition using APX analogs both in vitro and in vivo. Successful derailing of MPNST survival pathways by targeting Ref-1 redox function is our aim to treat this rare but deadly cancer.

Our findings help to elucidate the role played by APE1 in cervical cancer metastasis and targeting APE1 redox function may be a novel strategy for inhibiting cervical cancer metastasis.