A novel p21 attenuator which is structurally related to sorafenib

Hiromi I. Wettersten, Sung Hee Hwang, Cuiwen Li, Eunice Y. Shiu, Aaron T. Wecksler, Bruce D. Hammock, Robert H Weiss

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

p21 is a member of the cyclin kinase inhibitor family of proteins and plays pivotal roles in cellular proliferation as well as in the regulation of apoptosis, and thus has diverse functions in diseases as varied as cancer and atherosclerosis. In light of its pleiotropic effects and potential clinical relevance, new methods of attenuation of p21 protein levels by selective inhibitors are therefore powerful tools to probe malignant, infectious and other diseases. Here we introduce a novel p21 attenuator, UC2288, which possesses consistent and relatively selective activity for p21. UC2288 was synthesized based on the chemical model of sorafenib, a multikinase inhibitor that also attenuates p21, but unlike sorafenib, UC2288 did not inhibit Raf kinases or alter p-ERK protein levels. UC2288 decreased p21 mRNA expression independently of p53, and attenuated p21 protein levels with minimal effect on p21 protein stability. In addition, UC2288 inhibits cell growth in the kidney cancer cell lines (GI50 = approximately 10 μM) as well as multiple other cancer cell lines. Thus, this novel p21 inhibitor will be indispensable for exploring the function of p21, and upon further study may be translatable to the clinic.

Original languageEnglish (US)
Pages (from-to)278-285
Number of pages8
JournalCancer Biology and Therapy
Volume14
Issue number3
DOIs
StatePublished - Mar 2013

Fingerprint

Cyclin-Dependent Kinase Inhibitor Proteins
raf Kinases
Chemical Models
Cell Line
Proteins
Protein Stability
Kidney Neoplasms
Communicable Diseases
Neoplasms
Atherosclerosis
Cell Proliferation
sorafenib
UC2288
Apoptosis
Messenger RNA
Growth

Keywords

  • Apoptosis
  • P21
  • P21 inhibitor
  • Proliferation
  • Sorafenib

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

Cite this

Wettersten, H. I., Hwang, S. H., Li, C., Shiu, E. Y., Wecksler, A. T., Hammock, B. D., & Weiss, R. H. (2013). A novel p21 attenuator which is structurally related to sorafenib. Cancer Biology and Therapy, 14(3), 278-285. https://doi.org/10.4161/cbt.23374

A novel p21 attenuator which is structurally related to sorafenib. / Wettersten, Hiromi I.; Hwang, Sung Hee; Li, Cuiwen; Shiu, Eunice Y.; Wecksler, Aaron T.; Hammock, Bruce D.; Weiss, Robert H.

In: Cancer Biology and Therapy, Vol. 14, No. 3, 03.2013, p. 278-285.

Research output: Contribution to journalArticle

Wettersten, HI, Hwang, SH, Li, C, Shiu, EY, Wecksler, AT, Hammock, BD & Weiss, RH 2013, 'A novel p21 attenuator which is structurally related to sorafenib', Cancer Biology and Therapy, vol. 14, no. 3, pp. 278-285. https://doi.org/10.4161/cbt.23374
Wettersten HI, Hwang SH, Li C, Shiu EY, Wecksler AT, Hammock BD et al. A novel p21 attenuator which is structurally related to sorafenib. Cancer Biology and Therapy. 2013 Mar;14(3):278-285. https://doi.org/10.4161/cbt.23374
Wettersten, Hiromi I. ; Hwang, Sung Hee ; Li, Cuiwen ; Shiu, Eunice Y. ; Wecksler, Aaron T. ; Hammock, Bruce D. ; Weiss, Robert H. / A novel p21 attenuator which is structurally related to sorafenib. In: Cancer Biology and Therapy. 2013 ; Vol. 14, No. 3. pp. 278-285.
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