The c-Myc oncoprotein is overexpressed in many tumors and is essential for maintaining the proliferation of transformed cells. To function as a transcription factor, c-Myc must dimerize with Max via the basic helix-loop-helix leucine zipper protein (bHLH-ZIP) domains in each protein. 10074-G5 is a c-Myc inhibitor that binds to and distorts the bHLH-ZIP domain of c-Myc (Kd = 2.8 μM), thereby inhibiting c-Myc/Max heterodimer formation and inhibiting its transcriptional activity (IC50 = 146 μM). 10074-G5 is cytotoxic to c-Myc-overexpressing cells lines with IC50 values of 15.6 and 13.5 μM for Daudi Burkitt lymphoma cells and HL60 promyelocytic leukemia cells, respectively. 10074-G5 can also interfere with N-Myc/Max interactions (Kd = 19.2 μM for binding the bHLH-Zip of N-Myc), inducing apoptosis in N-Myc amplified neuroblastoma Kelly cells (IC50 = 22.5 μM).
