CREB-binding protein (CBP) KIX domain (CBP KIX)

The CREB-binding protein (CBP) KIX domain is a highly conserved protein-protein interaction module located within the transcriptional coactivator CBP (UniProt P45481). It serves as a critical docking site for various transcription factors, including CREB, c-Myb, MLL, and p53, thereby facilitating the assembly of the transcriptional machinery at specific gene promoters (PMID: 9342353). By mediating these interactions, the KIX domain plays a pivotal role in regulating gene expression programs involved in cell growth, differentiation, and memory formation. In many cancers, particularly acute myeloid leukemia (AML) and prostate cancer, the KIX domain is exploited by oncogenic transcription factors to drive aberrant gene expression (PMID: 26053138). Consequently, the KIX domain has emerged as a significant therapeutic target for the development of small-molecule inhibitors, such as KG-501, designed to disrupt these protein-protein interactions (PMID: 19158331). These inhibitors aim to block the binding of oncogenic drivers like Myb or MLL, potentially halting cancer progression. However, because CBP is involved in numerous physiological processes, achieving selectivity and avoiding systemic toxicity remain major challenges in drug development. Furthermore, the structural similarity between the KIX domains of CBP and its paralog p300 complicates the design of specific inhibitors.

Other names

CREBBP KIX domainKIX domain of CBPCBP/p300 KIX domain

Inhibition of protein-protein interactions between the KIX domain and transcription factors such as CREB, Myb, and MLL.