cAMP-responsive element-binding protein 1 (CREB1)

cAMP-responsive element-binding protein 1 (CREB1) is a critical leucine zipper transcription factor that integrates various cellular signals by binding to the cAMP-responsive element (CRE) in gene promoters (UniProt: P16220). It is activated primarily through phosphorylation at Serine-133 by protein kinase A (PKA) and other kinases in response to increased intracellular cAMP levels (PubMed: 28539207). CREB1 plays a fundamental role in the nervous system, where it is essential for the conversion of short-term memory into long-term memory and neuronal survival (StatPearls: NBK554477). In oncology, CREB1 is frequently overexpressed and acts as a proto-oncogene in various cancers, promoting tumor cell proliferation, resistance to apoptosis, and metastasis (PubMed: 32709230). While traditionally considered "undruggable" due to its nature as a transcription factor, current therapeutic strategies focus on disrupting its interaction with co-activators like CBP or inhibiting its DNA-binding capacity (PubMed: 31213506). Developing selective CREB1 inhibitors remains a significant challenge due to the protein's broad physiological roles and the risk of systemic toxicity, particularly regarding cognitive and metabolic functions (NIH: PMC7139178).

Other names

Cyclic AMP-responsive element-binding protein 1CREB-1Active transcription factor CREB

Small molecule inhibitors typically target the interaction between the CREB Kinase-Inducible Domain (KID) and the KIX domain of the co-activator CBP/p300, or block the DNA-binding activity of the bZIP domain to prevent transcription of downstream target genes.