Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity

Fuchun Xie, Bingbing X. Li, Alina Kassenbrock, Changhui Xue, Xiaoyan Wang, Zheng (David) Qian, Rosalie Sears, Xiangshu Xiao

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Recent studies have shown that nuclear transcription factor cyclic adenosine monophosphate response element binding protein (CREB) is overexpressed in many different types of cancers. Therefore, CREB has been pursued as a novel cancer therapeutic target. Naphthol AS-E and its closely related derivatives have been shown to inhibit CREB-mediated gene transcription and cancer cell growth. Previously, we identified naphthamide 3a as a different chemotype to inhibit CREB's transcription activity. In a continuing effort to discover more potent CREB inhibitors, a series of structural congeners of 3a was designed and synthesized. Biological evaluations of these compounds uncovered compound 3i (666-15) as a potent and selective inhibitor of CREB-mediated gene transcription (IC50 = 0.081 ± 0.04 μM). 666-15 also potently inhibited cancer cell growth without harming normal cells. In an in vivo MDA-MB-468 xenograft model, 666-15 completely suppressed the tumor growth without overt toxicity. These results further support the potential of CREB as a valuable cancer drug target.

Original languageEnglish (US)
Pages (from-to)5075-5087
Number of pages13
JournalJournal of Medicinal Chemistry
Volume58
Issue number12
DOIs
StatePublished - Jun 25 2015

Fingerprint

Genes
Neoplasms
Growth
CREB-Binding Protein
Neoplasm Genes
Response Elements
Heterografts
Cyclic AMP
Inhibitory Concentration 50
Transcription Factors
Pharmaceutical Preparations
Therapeutics
naphthol AS-E

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity. / Xie, Fuchun; Li, Bingbing X.; Kassenbrock, Alina; Xue, Changhui; Wang, Xiaoyan; Qian, Zheng (David); Sears, Rosalie; Xiao, Xiangshu.

In: Journal of Medicinal Chemistry, Vol. 58, No. 12, 25.06.2015, p. 5075-5087.

Research output: Contribution to journalArticle

@article{e869e2c2710c40c3934d2a74767750e3,
title = "Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity",
abstract = "Recent studies have shown that nuclear transcription factor cyclic adenosine monophosphate response element binding protein (CREB) is overexpressed in many different types of cancers. Therefore, CREB has been pursued as a novel cancer therapeutic target. Naphthol AS-E and its closely related derivatives have been shown to inhibit CREB-mediated gene transcription and cancer cell growth. Previously, we identified naphthamide 3a as a different chemotype to inhibit CREB's transcription activity. In a continuing effort to discover more potent CREB inhibitors, a series of structural congeners of 3a was designed and synthesized. Biological evaluations of these compounds uncovered compound 3i (666-15) as a potent and selective inhibitor of CREB-mediated gene transcription (IC50 = 0.081 ± 0.04 μM). 666-15 also potently inhibited cancer cell growth without harming normal cells. In an in vivo MDA-MB-468 xenograft model, 666-15 completely suppressed the tumor growth without overt toxicity. These results further support the potential of CREB as a valuable cancer drug target.",
author = "Fuchun Xie and Li, {Bingbing X.} and Alina Kassenbrock and Changhui Xue and Xiaoyan Wang and Qian, {Zheng (David)} and Rosalie Sears and Xiangshu Xiao",
year = "2015",
month = "6",
day = "25",
doi = "10.1021/acs.jmedchem.5b00468",
language = "English (US)",
volume = "58",
pages = "5075--5087",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "12",

}

TY - JOUR

T1 - Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity

AU - Xie, Fuchun

AU - Li, Bingbing X.

AU - Kassenbrock, Alina

AU - Xue, Changhui

AU - Wang, Xiaoyan

AU - Qian, Zheng (David)

AU - Sears, Rosalie

AU - Xiao, Xiangshu

PY - 2015/6/25

Y1 - 2015/6/25

N2 - Recent studies have shown that nuclear transcription factor cyclic adenosine monophosphate response element binding protein (CREB) is overexpressed in many different types of cancers. Therefore, CREB has been pursued as a novel cancer therapeutic target. Naphthol AS-E and its closely related derivatives have been shown to inhibit CREB-mediated gene transcription and cancer cell growth. Previously, we identified naphthamide 3a as a different chemotype to inhibit CREB's transcription activity. In a continuing effort to discover more potent CREB inhibitors, a series of structural congeners of 3a was designed and synthesized. Biological evaluations of these compounds uncovered compound 3i (666-15) as a potent and selective inhibitor of CREB-mediated gene transcription (IC50 = 0.081 ± 0.04 μM). 666-15 also potently inhibited cancer cell growth without harming normal cells. In an in vivo MDA-MB-468 xenograft model, 666-15 completely suppressed the tumor growth without overt toxicity. These results further support the potential of CREB as a valuable cancer drug target.

AB - Recent studies have shown that nuclear transcription factor cyclic adenosine monophosphate response element binding protein (CREB) is overexpressed in many different types of cancers. Therefore, CREB has been pursued as a novel cancer therapeutic target. Naphthol AS-E and its closely related derivatives have been shown to inhibit CREB-mediated gene transcription and cancer cell growth. Previously, we identified naphthamide 3a as a different chemotype to inhibit CREB's transcription activity. In a continuing effort to discover more potent CREB inhibitors, a series of structural congeners of 3a was designed and synthesized. Biological evaluations of these compounds uncovered compound 3i (666-15) as a potent and selective inhibitor of CREB-mediated gene transcription (IC50 = 0.081 ± 0.04 μM). 666-15 also potently inhibited cancer cell growth without harming normal cells. In an in vivo MDA-MB-468 xenograft model, 666-15 completely suppressed the tumor growth without overt toxicity. These results further support the potential of CREB as a valuable cancer drug target.

UR - http://www.scopus.com/inward/record.url?scp=84933059416&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84933059416&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.5b00468

DO - 10.1021/acs.jmedchem.5b00468

M3 - Article

VL - 58

SP - 5075

EP - 5087

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 12

ER -