Letter abstract


Nature Chemical Biology 2, 369 - 374 (2006)
Published online: 11 June 2006 | Corrected online: 1 October 0613 | doi:10.1038/nchembio800



There is a Corrigendum (February 2007) associated with this Letter.

There is a Retraction (July 2008) associated with this Letter.

Small molecule–based reversible reprogramming of cellular lifespan

Jaejoon Won1, Mina Kim1,2,5, Nuri Kim1,5, Jin Hee Ahn3, Woo Gil Lee3, Sung Soo Kim3, Ki-Young Chang1, Yong-Weon Yi1 & Tae Kook Kim1,4

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Most somatic cells encounter an inevitable destiny, senescence1, 2. Little progress has been made in identifying small molecules that extend the finite lifespan of normal human cells. Here we show that the intrinsic 'senescence clock' can be reset in a reversible manner by selective modulation of the ataxia telangiectasia–mutated (ATM) protein and ATM- and Rad3-related (ATR) protein with a small molecule, CGK733. This compound was identified by a high-throughput phenotypic screen with automated imaging. Employing a magnetic nanoprobe technology, magnetism-based interaction capture (MAGIC)3, we identified ATM as the molecular target of CGK733 from a genome-wide screen. CGK733 inhibits ATM and ATR kinase activities and blocks their checkpoint signaling pathways with great selectivity. Consistently, siRNA-mediated knockdown of ATM and ATR induced the proliferation of senescent cells, although with lesser efficiency than CGK733. These results might reflect the specific targeting of the kinase activities of ATM and ATR by CGK733 without affecting any other domains required for cell proliferation.

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  1. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea
  2. CGK Co., Ltd., Daejeon Bioventure Town, Daejeon 305-811, Korea.
  3. Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea.
  4. Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-600, Korea.
  5. These authors contributed equally to this work.

Correspondence to: Tae Kook Kim1,4 e-mail: tkkim@kaist.ac.kr

* negative CFI should have been instead a positive CFI - added new CFI, HTML note, and updated PDF

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