Background:

666-15 is a potent and selective CREB inhibitor with an IC50 of 81 nM.

666-15 potently inhibits cancer cell growth. In MDA-MB-231 and MDA-MB-468 cells, the GI50 for 666-15 is 73 and 46 nM, respectively. In A549 and MCF-7 cells, it exhibits robust activity as well with GI50 of 0.47 and 0.31 μM. 666-15 is also found to be a rather weak inhibitor of CREB-CBP interaction with IC50 of 18.27 μM. 666-15 inhibits CREB’s transcription activity in living cells independent of direct CREB or CBP binding interaction. 666-15 is very potent in inhibiting CREB’s transcription activity. 666-15 also inhibits endogenous CREB target gene expression, the transcript level of nuclear receptor related 1 protein (Nurr1/NR4A2)[1].

Preliminary toxicity studies show that intraperitoneal (ip) injection of 10 mg/kg of 666-15 is well tolerated in mice. The tumor growth in the mice treated with 666-15 is efficaciously inhibited with complete tumor stasis. During the same period, the tumor volume in the vehicle-treated group is more than tripled. The body weights of 666-15-treated animals and vehicle-treated ones are indistinguishable from each other during the entire treatment period[1].

[1]. Xie F, et al. Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity. J Med Chem. 2015 Jun 25;58(12):5075-87.