p53 Inhibitors

No.161(April 2014)

C2826: Cyclic Pifithrin-α Hydrobromide (1)
P2048: Pifithrin-μ (= 2-Phenylethynesulfonamide) (2)

p53 (Also known as Trp53 in mice, TP53 in humans) is a tumor suppressor protein that is frequently inactivated in tumors.¹⁾ It has been revealed that inhibition of p53 can improve the reprogramming efficiency of human and mouse somatic cells.^2-7) The protein has been focused on in the research field.⁸⁾

Pifithrins are inhibitors of p53. Pifithrin-α is a transcriptional inhibitor of p53 and rapidly converts to the condensation form, cyclic-pifithrin-α (1, also called pifithrin-β).⁹⁾. Pifithrin-μ (2) was initially identified as a small-molecule inhibitor of the binding of p53 to mitochondria by reducing its affinity to antiapoptic proteins Bcl-xL and Bcl-2.¹⁰⁾.

References

1)Assessing TP53 status in human tumours to evaluate clinical outcome
- T. Soussi, C. Béroud, Nat. Rev. Cancer 2001, 1, 233.
2)Two supporting factors greatly improve the efficiency of human iPSC generation
- Y. Zhao, X. Yin, H. Qin, F. Zhu, H. Liu, W. Yang, Q. Zhang, C. Xiang, P. Hou, Z. Song, Y. Liu, J. Yong, P. Zhang, J. Cai, M. Liu, H. Li, Y. Li, X. Qu, K. Cui, W. Zhang, T. Xiang, Y. Wu, Y. Zhao, C. Liu, C. Yu, K. Yuan, J. Lou, M. Ding, H. Deng, Cell Stem Cell 2008, 3, 475.
3)Suppression of Induced pluripotent stem cell generation by the p53-p21 pathway
- H. Hong, K. Takahashi, T. Ichisaka, T. Aoi, O. Kanagawa, M. Nakagawa, K. Okita, S. Yamanaka, Nature 2009, 460, 1132.
4)The Ink4/Arf locus is a barrier for iPS reprogramming
- H. Li, M. Collado, A. Villasante, K. Strati, S. Ortega, M. Cañamero, M. A. Blasco, M. Serrano, Nature 2009, 460, 1136.
5)Linking the p53 tumour suppressor pathway to somatic cell reprogramming
- T. Kawamura, J. Suzuki, Y. V. Wang, S. Menendez, L. B. Morera, A. Raya, G. M. Wahl, J. C. I. Belmonte, Nature 2009, 460, 1140.
6)Immortalization eliminates a roadblock during cellular reprogramming into iPS cells
- J. Utikal, J. M. Polo, M. Stadtfeld, N. Maherali, W. Kulalert, R. M. Walsh, A. Khalil, J. G. Rheinwald, K. Hochedlinger, Nature 2009, 460, 1145.
7)A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity
- R. M. Marión, K. Strati, H. Li, M. Murga, R. Blanco, S. Ortega, O. Fernandez-Capetillo, M. Serrano, M. A. Blasco, Nature 2009, 460, 1149.
8)p53, Stem cells, and reprogramming: tumor suppression beyond guarding the genome
- B. T. Spike, G. M. Wahl, Genes & Cancer 2011, 2, 404.
9)A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy
- P. G. Komarov, E. A. Komarova, R. V. Kondratov, K. Christov-Tselkov, J. S. Coon, M. V. Chernov, A. V. Gudkov, Science 1999, 285, 1733.
10)Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation
- E. Strom, S. Sathe, P. G. Komarov, O. B. Chernova, I. Pavlovska, I. Shyshynova, D. A. Bosykh, L. G. Burdelya, R. M. Macklis, R. Skaliter, E. A. Komarova, A.V. Gudkov, Nat. Chem. Biol. 2006, 2, 474.

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