The following assay summarizes ongoing efforts in the development of chemical probes that inhibit human Tyrosyl-DNA Phosphodiesterase (Tdp1). ..more
Target
Depositor Specified Assays
| AID | Name | Type | Comment |
|---|---|---|---|
| 485290 | qHTS Assay for Inhibitors of Tyrosyl-DNA Phosphodiesterase (TDP1) | confirmatory | qHTS Assay |
| 492989 | Gel-Based Assay for Inhibitors of Tyrosyl-DNA Phosphodiesterase (TDP1) | confirmatory | Gel-Based Assay for Inhibitors of Tyrosyl-DNA Phosphodiesterase |
| 489007 | Confirmation Assay for Inhibitors of Tyrosyl-DNA Phosphodiesterase (TDP1) | confirmatory | |
| 492990 | Gel-Based Assay for Inhibitors of HIV Integrase: Counterscreen for TDP1 | confirmatory | Gel-Based Assay for Inhibitors of HIV Integrase |
| 504474 | Gel-Based Assay for Inhibitors of Tyrosyl-DNA Phosphodiesterase (TDP1): Hit Validation | confirmatory | |
| 504464 | Gel-Based Assay for Inhibitors of HIV Integrase: Hit Validation Counterscreen for TDP1 Inhibitors | confirmatory |
Description:
The following assay summarizes ongoing efforts in the development of chemical probes that inhibit human Tyrosyl-DNA Phosphodiesterase (Tdp1).
Tdp1 is a novel human enzyme that is involved in the repair of DNA lesions created by the trapping of DNA topoisomerase I (Top1) following treatment by anticancer agents, such as camptothecins and indenoisoquinolines. Only a limited number of weak inhibitors have been reported for Tdp1. These inhibitors have much literature precedent and have been found to exhibit a wide variety of promiscuous biological activity. Aminoglycoside antibiotics and ribosome inhibitors were reported as millimolar Tdp1 inhibitors. More recently, an electrochemiluminescent (ECL) assay was used to screen the NCI Developmental Therapeutics Program (DTP) plated-compound sets. Furamidine (NSC 305831, PubChem CID: 126437) was reported to inhibit Tdp1 at micromolar concentration but may have additional targets due to its noted DNA-binding properties. Recently, a C21-substituted progesterone derivative, NSC88915, has been reported to possess specific Tdp1 inhibitory activity. However, the compound was also estimated to be a micromolar inhibitor in both the ECL assay and a gel-based assay that utilized a radiolabeled substrate. Thus, there is an unmet need to identify novel, potent chemotypes with a range of analogues to determine SAR. The large and diverse MLSMR collection is ideally suited for a screen for inhibitors of Tdp1 to find novel chemotypes.
Tdp1 is a novel human enzyme that is involved in the repair of DNA lesions created by the trapping of DNA topoisomerase I (Top1) following treatment by anticancer agents, such as camptothecins and indenoisoquinolines. Only a limited number of weak inhibitors have been reported for Tdp1. These inhibitors have much literature precedent and have been found to exhibit a wide variety of promiscuous biological activity. Aminoglycoside antibiotics and ribosome inhibitors were reported as millimolar Tdp1 inhibitors. More recently, an electrochemiluminescent (ECL) assay was used to screen the NCI Developmental Therapeutics Program (DTP) plated-compound sets. Furamidine (NSC 305831, PubChem CID: 126437) was reported to inhibit Tdp1 at micromolar concentration but may have additional targets due to its noted DNA-binding properties. Recently, a C21-substituted progesterone derivative, NSC88915, has been reported to possess specific Tdp1 inhibitory activity. However, the compound was also estimated to be a micromolar inhibitor in both the ECL assay and a gel-based assay that utilized a radiolabeled substrate. Thus, there is an unmet need to identify novel, potent chemotypes with a range of analogues to determine SAR. The large and diverse MLSMR collection is ideally suited for a screen for inhibitors of Tdp1 to find novel chemotypes.
Protocol
Please see related assay AID 489007 for a detailed protocol.
Comment
Compound ranking comments will be added here as small molecule probes are developed and are annotated with bioassays in PubChem.
Additional Information
Grant Number: MH089814-01
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