Developing novel therapeutics often follows three steps: target identification, design of
strategies to suppress target activity and drug development to implement the strategies. In this
review, we re Show more
Developing novel therapeutics often follows three steps: target identification, design of
strategies to suppress target activity and drug development to implement the strategies. In this
review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5,
CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit
the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that
selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides
(CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating
domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show
both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo,
and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known
mechanisms by which the peptides act and how these have been exploited in rationally designed
combination therapies. We additionally discuss lacunae in our knowledge about the peptides that
merit further research. Finally, we suggest both short- and long-term directions for creating new
generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating
brain and other malignancies.
Citation: Greene, L.A.; Zhou, Q.;
Siegelin, M.D.; Angelastro, J.M.
Targeting Transcription Factors ATF5, Show less