Small Molecule Inhibitors of Human DNA Polymerase λ | Zendy

Tobias Strittmatter | Zendy; Bettina Bareth | Zendy; Timo A. Immel | Zendy; Thomas Huhn | Zendy; Thomas U. Mayer | Zendy; Andreas Marx | Zendy

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Small Molecule Inhibitors of Human DNA Polymerase λ

Author(s) -

Tobias Strittmatter,

Bettina Bareth,

Timo A. Immel,

Thomas Huhn,

Thomas U. Mayer,

Andreas Marx

Publication year - 2010

Publication title -

acs chemical biology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.899

H-Index - 111

eISSN - 1554-8937

pISSN - 1554-8929

DOI - 10.1021/cb100382m

Subject(s) - dna polymerase , polymerase , dna , dna clamp , dna polymerase ii , biology , computational biology , drug discovery , dna polymerase beta , enzyme , small molecule , biochemistry , microbiology and biotechnology , chemistry , genetics , dna repair , polymerase chain reaction , reverse transcriptase , gene , base excision repair

To discover chemical probes to further under-stand the function of individual DNA polymerases, we established a generally applicable high-throughput screening. By applying this technique we discovered three novel inhibitor classes of human DNA polymerase λ (DNA Pol λ), a key enzyme to maintain the genetic integrity of the genome. The rhodanines, classified as an excellent drug scaffold, were found to be the most potent inhibitors for DNA Pol λ. Importantly, they are up to 10 times less active against the highly similar DNA polymerase β. We investigated basic structure activity relationships. Furthermore, the rhodanines showed pharmacological activity in two human cancer cell lines. So the here reported small molecules could serve as useful DNA Pol λ probes and might serve as starting point to develop novel therapeutic agents.

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