Abstract
Control of NF-κB release through the inhibition of I & κB kinase β (IKKβ) has been identified as a potential target for the treatment of inflammatory and autoimmune diseases. To screen the small molecule compound library against IKKβ, a high throughput screening (HTS) campaign was carried out using immobilized metal affinity for phosphochemicals (IMAP)-based time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Through serial optimization of assay conditions, the Z value was achieved at 0.88 from the pilot library screening of the most diverse 7,243 compounds with reconfirmation rate of 63%. The results from this HTS campaign identified three novel scaffolds for the prospective IKKβ inhibitor, such as 7-benzoyl-4-phenylcyclopenta [1,2] oxazine, 1-(thiophen or furan)-2,3- dihydroimidazo[1,5] pyridine and 2-phenyloxazolo [5,4] pyridine. Particularly, 7-benzoyl-4-phenylcyclopenta [1,2] oxazine derivatives presented potent inhibitory activity and selectivity for IKKβ. These findings suggest that the current TR-FRET assay system for IKKβ was successful to identify hits for novel IKKβ inhibitors as a robust, reproducible and sensitive HTS system.
Keywords: IκB kinase β, IKKβ inhibitor, time-resolved fluorescence resonance energy transfer.
Combinatorial Chemistry & High Throughput Screening
Title: Identification of Novel Scaffolds for IκB Kinase Beta Inhibitor via a High Throughput Screening TR-FRET Assay
Volume: 13 Issue: 9
Author(s): Kwang-Seok Oh, Sunghou Lee, Joong Kwon Choi and Byung Ho Lee
Affiliation:
Keywords: IκB kinase β, IKKβ inhibitor, time-resolved fluorescence resonance energy transfer.
Abstract: Control of NF-κB release through the inhibition of I & κB kinase β (IKKβ) has been identified as a potential target for the treatment of inflammatory and autoimmune diseases. To screen the small molecule compound library against IKKβ, a high throughput screening (HTS) campaign was carried out using immobilized metal affinity for phosphochemicals (IMAP)-based time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Through serial optimization of assay conditions, the Z value was achieved at 0.88 from the pilot library screening of the most diverse 7,243 compounds with reconfirmation rate of 63%. The results from this HTS campaign identified three novel scaffolds for the prospective IKKβ inhibitor, such as 7-benzoyl-4-phenylcyclopenta [1,2] oxazine, 1-(thiophen or furan)-2,3- dihydroimidazo[1,5] pyridine and 2-phenyloxazolo [5,4] pyridine. Particularly, 7-benzoyl-4-phenylcyclopenta [1,2] oxazine derivatives presented potent inhibitory activity and selectivity for IKKβ. These findings suggest that the current TR-FRET assay system for IKKβ was successful to identify hits for novel IKKβ inhibitors as a robust, reproducible and sensitive HTS system.
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Cite this article as:
Oh Kwang-Seok, Lee Sunghou, Kwon Choi Joong and Ho Lee Byung, Identification of Novel Scaffolds for IκB Kinase Beta Inhibitor via a High Throughput Screening TR-FRET Assay, Combinatorial Chemistry & High Throughput Screening 2010; 13 (9) . https://dx.doi.org/10.2174/138620710792927367
DOI https://dx.doi.org/10.2174/138620710792927367 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
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