Small molecule-based reversible reprogramming of cellular lifespan.

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.
Authors	Jaejoon Won, Mina Kim, Nuri Kim, Jin Hee Ahn, Woo Gil Lee, Sung Soo Kim, Ki-Young Chang, Yong-Weon Yi, Tae Kook Kim
Journal	Nature chemical biology (Nat Chem Biol) Vol. 2 Issue 7 Pg. 369-74 (Jul 2006) ISSN: 1552-4450 [Print] United States
PMID	16767085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)
Chemical References	Benzeneacetamides CGK 733 Cell Cycle Proteins DNA-Binding Proteins Tumor Suppressor Proteins ATM protein, human ATR protein, human Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Thiourea
Topics	Ataxia Telangiectasia Mutated Proteins Benzeneacetamides (chemistry, pharmacology) Cell Cycle (drug effects) Cell Cycle Proteins (metabolism) Cell Line Cellular Senescence (drug effects, physiology) DNA-Binding Proteins (metabolism) Humans Molecular Structure Protein Serine-Threonine Kinases (metabolism) Signal Transduction (drug effects) Thiourea (analogs & derivatives, chemistry, pharmacology) Tumor Suppressor Proteins (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!