Breast cancer is a heterogeneous group of diseases with distinct and complex mechanisms of pathogenesis. Triple-negative breast cancers (TNBC) form a subgroup of breast cancers with poor prognosis. TNBCs lack the expression of estrogen receptor (ER), progesterone receptor (PR) or HER2 and no targeted therapies exist. The cAMP response element binding protein (CREB) is a stimulus-induced transcription factor activated by multiple extracellular signals through phosphorylation. The phosphorylated CREB (p-CREB) can then bind the mammalian transcription co-activator, CREB-binding protein (CBP). This binding event will further recruit other transcriptional machinery to the gene promoter to initiate CREB-dependent gene transcription. CREB is overexpressed in breast cancer tissues compared to normal mammary tissues and the level of expression inversely correlates with disease-free survival. We present here the discovery of a potent small molecule inhibitor of CREB-mediated gene transcription with in vitro and in vivo activity in TNBCs. Starting from 1  , which is a low micromolar and cell-permeable inhibitor of CREB-mediated gene transcription, we designed and synthesized 2 . Compound 2  potently inhibited CREB-mediated gene transcription with IC50 ~80 nM. This compound potently inhibited proliferation of MDA-MB-231 and MDA-MB-468 cells. In contrast, compound 2  was not toxic to normal human cells. In vivo, compound 2  completely suppressed the growth of MDA-MB-468 cells without toxicity. These results suggest that compound 2  is a potent CREB inhibitor warranting further development as an anti-breast cancer agent.

Discovery of a potent inhibitor of CREB-mediated gene transcription with growth inhibitory activity in triple-negative breast cancer

246th National Meeting (2013)

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