Systemic Inhibition of CREB is Well-tolerated in vivo.
cAMP-response element binding protein (CREB) is a nuclear transcription factor activated by multiple extracellular signals including growth factors and hormones. These extracellular cues activate CREB through phosphorylation at Ser133 by various protein serine/threonine kinases. Once phosphorylated, it promotes its association with transcription coactivators CREB-binding protein (CBP) and its paralog p300 to activate CREB-dependent gene transcription. Tumor tissues of different origins have been shown to present overexpression and/or overactivation of CREB, indicating CREB as a potential cancer drug target. We previously identified 666-15 as a potent inhibitor of CREB with efficacious anti-cancer activity both in vitro and in vivo. Herein, we investigated the specificity of 666-15 and evaluated its potential in vivo toxicity. We found that 666-15 was fairly selective in inhibiting CREB. 666-15 was also found to be readily bioavailable to achieve pharmacologically relevant concentrations for CREB inhibition. Furthermore, the mice treated with 666-15 showed no evidence of changes in body weight, complete blood count, blood chemistry profile, cardiac contractility and tissue histologies from liver, kidney and heart. For the first time, these results demonstrate that pharmacological inhibition of CREB is well-tolerated in vivo and indicate that such inhibitors should be promising cancer therapeutics.
Program in Chemical Biology, Department of Physiology and Pharmacology, Oregon Health &Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
Bingbing X
BX
Li
Program in Chemical Biology, Department of Physiology and Pharmacology, Oregon Health &Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
Ryan
R
Gardner
Knight Cancer Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
Changhui
C
Xue
Knight Cancer Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
David Z
DZ
Qian
Program in Chemical Biology, Department of Physiology and Pharmacology, Oregon Health &Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
Fuchun
F
Xie
Knight Cancer Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
George
G
Thomas
Department of Pathology, Oregon Health &Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
Steven C
SC
Kazmierczak
Program in Chemical Biology, Department of Physiology and Pharmacology, Oregon Health &Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.|Knight Cardiovascular Institute, Department of Medicine, Oregon Health &Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
Beth A
BA
Habecker
Program in Chemical Biology, Department of Physiology and Pharmacology, Oregon Health &Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.|Knight Cancer Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.|Knight Cardiovascular Institute, Department of Medicine, Oregon Health &Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
Xiangshu
X
Xiao
D000813:Anilides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009281:Naphthalenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
C000621942:666-15 compound; D000813:Anilides; D000970:Antineoplastic Agents; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D009281:Naphthalenes; D009363:Neoplasm Proteins
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