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Small Molecule-Based Reversible Reprogramming of Cellular Lifespan

Small Molecule-Based Reversible Reprogramming of Cellular Lifespan

Jaejoon Won, Mina Kim, Nuri Kim, Jin Hee Ahn, Woo Gil Lee, Sung Soo Kim, Ki-Young Chang, Yong-Weon Yi, Tae Kook Kim

Nat Chem Biol. 2006 Jul;2(7):369-74.

PMID: 16767085

Abstract:

Most somatic cells encounter an inevitable destiny, senescence. 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), 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4242694	CGK733			Price

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