The transcription factor Max is a basic helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. The asymmetric polycyclic lactam, KI-MS2-008, binds Max and stabilizes Max homodimers while reducing Myc protein and Myc-regulated transcript levels. KI-MS2-008 decreases viable Myc-dependent cancer cell levels and exhibits efficacy in vivo by reducing tumor burden, thus demonstrating the feasibility of altering Max dimerization as an alternative approach to targeting Myc.

From a small molecule microarray screen against purified Max, we prioritized the DOS polycyclic lactam BRD-K19261677 (KI-MS2-001) due to validated potency upon resynthesis and reasonable physicochemical characteristics. Structure activity relationship studies led to the development of KI-MS2-008, which is an unoptimized chemical probe with a cLogP of 6.38. Because the compound has limited water solubility, we typically work at 1 – 10 µM concentrations and do not recommend utilizing concentrations >50 µM.