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KG-501 is a CREB inhibitor, with an IC50 of 6.89 μM.

KG-501, which directly targets the KIX domain of CBP, results in a disrupted CREB-CBP complex, inhibits CREB-target gene induction, and inhibits IL-1β-mediated angiogenic activity in NSCLC[1]. KG-501 disrupts phospho (Ser-133) CREB binding to KIX with a Ki of ~90 μM, using concentrations of CREB that are within the linear range of the binding assay. Treatment of HEK293T cells with KG-501 also blocks induction of endogenous CREB target genes (NR4A2, αCG, c-fos, and RGS2) by forskolin, indicating that KG-501 likely exerts a general effect on CREB activity[2]. KG-501 can also inhibit NF-κB transcription activity because NF-κB also uses CBP as a cofactor to regulate gene expression. The migration of HUVECs induced by CM from A549 cells treated with IL-1β plus 10 μM of KG-501 is significantly lower than that induced by CM from A549 cells treated with IL-1β alone. At 10 μM, KG-501 suppresses the expression of all of the IL-1β-induced CXC chemokine genes except CXCL8. For the protein level, KG-501 significantly suppresses IL-1β-induced CXCL5 protein secretion. Similar effects of KG-501 are also observed in the H1734 cell line[3].

[1]. Lee JW, et al. A Novel Small-Molecule Inhibitor Targeting CREB-CBP Complex Possesses Anti-Cancer Effects along with Cell Cycle Regulation, Autophagy Suppression and Endoplasmic Reticulum Stress. PLoS One. 2015 Apr 21;10(4):e0122628. [2]. Best JL et al. Identification of small-molecule antagonists that inhibit an activator: coactivator interaction. Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17622-7 [3]. Sun H, et al. Cyclic AMP-responsive element binding protein- and nuclear factor-kappaB-regulated CXC chemokine gene expression in lung carcinogenesis. Cancer Prev Res (Phila). 2008 Oct;1(5):316-28.

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