New Ref-1/APE1 targeted inhibitors demonstrating improved potency for clinical applications in multiple cancer types

• DOI: 10.1016/j.phrs.2024.107092
• Publication Date: 2024-02-02T17:27:12Z
• Authors: Silpa Gampala; Hye-ran Moon; Randall Wireman; Jacqueline Peil; Sonia Kiran; Dana K. Mitchell; Kylee Brewster; Henry Mang; Andi Masters; Christine Bach; Whitney Smith-Kin...; Emma H. Doud; Ratan Rai; Amber L. Mosley; Sara K. Quinney; D. Wade Clapp; Chafiq Hamdouchi; James Wikel; Chi Zhang; Bumsoo Han; Millie M. Georgiadis; Mark R. Kelley; Melissa L. Fishel
• Keywords: Hypoxia Inducible Factor 1 (HIF1α); 0301 basic medicine; Novel targeted inhibitors; 03 medical and health sciences; Therapeutics. Pharmacology; RM1-950; Potency; Cancers; Ref-1 redox function; Article; Nuclear Factor kappa B (NFκB)

AP endonuclease-1/Redox factor-1 (APE1/Ref-1 or Ref-1) is a multifunctional protein that overexpressed in most aggressive cancers and impacts various cancer cell signaling pathways. Ref-1's redox activity plays significant role activating transcription factors (TFs) such as NFκB, HIF1α, STAT3 AP-1, which are crucial contributors to the development of tumors metastatic growth. Therefore, potent, selective inhibitors target Ref-1 function an appealing approach for therapeutic intervention. A first-generation compound, APX3330 successfully completed phase I clinical trial adults with progressing solid favorable response rate, pharmacokinetics (PK), minimal toxicity. These positive results prompted us develop more potent analogs effectively tumors. In this study, we present structure-activity relationship (SAR) identification validation lead compounds exhibit greater potency similar better safety profile APX3330. order triage characterize on-target second-generation inhibitors, assayed PK, mouse human S9 fraction metabolic stability, silico ADMET properties, ligand-based WaterLOGSY NMR measurements, pharmacodynamic markers, viability multiple types, two distinct 3-dimensional (3D) killing assays (Tumor-Microenvironment on Chip 3D spheroid). To effects inhibition vivo, global proteomics was used following treatment top four analogs. This study identified characterized (that outperformed by 5-10-fold) PK studies demonstrating efficacious doses translation clinic.