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BioAssay: AID 463083

Summary of the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4)

Name: Summary of the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4) ..more
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AID: 463083
Data Source: The Scripps Research Institute Molecular Screening Center (PAD4_INH_SUMMARY)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2010-08-04
Modify Date: 2012-12-11
Target
Depositor Specified Assays
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AIDNameTypeComment
463073Fluorescence polarization-based primary biochemical high throughput screening assay to identify inhibitors of Protein Arginine Deiminase 4 (PAD4)screeningPrimary screen (PAD4 inhibitors in singlicate, NIH Validation Colletion)
485272Fluorescence polarization-based primary biochemical high throughput screening assay to identify inhibitors of Protein Arginine Deiminase 4 (PAD4) (1536 HTS)screeningPrimary screen (PAD4 inhibitors in singlicate)
488796Fluorescence polarization-based biochemical high throughput confirmation assay for inhibitors of Protein Arginine Deiminase 4 (PAD4)screeningConfirmation screen (PAD4 inhibitors in triplicate)
492970Fluorescence-based biochemical dose response assay to identify inhibitors of Protein Arginine Deiminase 4 (PAD4)confirmatoryDose response (PAD4 inhibitors in duplicate)
588416Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to assess potency of compound 16 against PAD4confirmatoryLate stage dose response (potency of compound 16 against PAD4 in duplicate)
588417Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to assess potency of compound 15 against PAD4confirmatoryLate stage dose response (potency of compound 15 against PAD4 in duplicate)
588418Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to assess potency of compound 13 against PAD4confirmatoryLate stage dose response (potency of compound 13 against PAD4 in duplicate)
588419Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to assess potency of compound 12 against PAD4confirmatoryLate stage dose response (potency of compound 12 against PAD4 in duplicate)
588420Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to assess potency of compound 11 against PAD4confirmatoryLate stage dose response (potency of compound 11 against PAD4 in duplicate)
588421Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical assay to assess potency of compound 6 against PAD4confirmatoryLate stage dose response (potency of compound 6 against PAD4 in duplicate)
588422Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical assay to assess potency of compound 2 against PAD4confirmatoryLate stage dose response (potency of compound 2 against PAD4 in duplicate)
588423Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to assess potency of compound 18 against PAD4confirmatoryLate stage dose response (potency of compound 18 against PAD4 in duplicate)
588438Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to assess potency of compound 1 against PAD1-4confirmatoryLate stage dose response (compound 1 potency against PAD1-4 in duplicate)
588462Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to assess potency of streptonigrin against PAD1-3confirmatoryLate stage dose response (streptonigrin potency against PAD1-4 in duplicate)
588471Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to assess potency of compound 3 against PAD1-4confirmatoryLate stage dose response (compound 3 potency against PAD1-4 in duplicate)
588472Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to assess potency of compound 14 against PAD1-4confirmatoryLate stage dose response (compound 14 potency against PAD1-4 in duplicate)
588484Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to assess potency of compound 10 against PAD1-4confirmatoryLate stage dose response (compound 10 potency against PAD1-4 in duplicate)
588486Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to assess potency of compound 21 against PAD1-4confirmatoryLate stage dose response (compound 21 potency against PAD1-4 in duplicate)
588487Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) inhibition by HTS hits of PADs 1-4otherLate stage assay (ABPP inhibition by HTS hits of PADs 1-4 in singlicate)
588488Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to assess potency of HTS hits against PAD1-4otherLate stage assay (compound 17 potency against PAD1-4 in duplicate)
588490Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to assess potency of compound 17 against PAD1-4confirmatoryLate stage dose response (HTS hits potency against PAD1-4 in singlicate)
588559Late stage assay provider results from the probe development effort to identify inhibitors of Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to identify inhibitors of PAD4otherLate stage results (PAD4 inhibitors in singlicate)
588560Late stage assay provider results from the probe development effort to identify inhibitors of PAD4: colorimetric biochemical substrate assay to identify inhibitors of PADs 1-4otherLate stage results (PAD1-4 inhibitors in singlicate)
651627Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate dialysis assay to assess binding mode of test compounds to PAD4otherLate stage assay (binding mode of test compounds to PAD4)
651628Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): fluorescence-based biochemical gel-based competitive Activity-Based Protein Profiling (ABPP) assessment of compound selectivityotherLate stage assay (compound selectivity)
651861Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate dialysis assay to assess binding mode of test compounds to PADs 1-3otherLate stage assay (binding mode of test compounds to PADs 1-3)
651865Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to determine rate constants of test compounds for PAD 2 inactivationotherLate stage assay (rate constants of test compounds for PAD2 inactivation)
651866Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to determine rate constants of test compounds for PAD 3 inactivationotherLate stage assay (rate constants of test compounds for PAD3 inactivation)
651867Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to determine rate constants of test compounds for PAD 4 inactivationotherLate stage assay (rate constants of test compounds for PAD4 inactivation)
651868Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): colorimetric biochemical substrate assay to determine rate constants of test compounds for PAD 1 inactivationotherLate stage assay (rate constants of test compounds for PAD1 inactivation)
651887Late stage assay provider results from the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4): cell-based absorbance-based assay to assess cytotoxicity of test compoundsconfirmatoryLate stage assay (cytotoxicity)
Description:
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Paul Thompson, University of South Carolina
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: R01 GM079357-01
Grant Proposal PI: Paul Thompson
External Assay ID: PAD4_INH_SUMMARY

Name: Summary of the probe development effort to identify inhibitors of Protein Arginine Deiminase 4 (PAD4)

Description:

RA is a chronic and progressive autoimmune disorder that affects about one percent of the US population [1]. Existing therapies treat the symptoms of the disease but not the underlying cause, and are associated with numerous side effects [2]. The activity of Protein Arginine Deiminase 4 (PAD4), one of four known active PAD isozymes, is increased in Rheumatoid Arthritis (RA); where it is thought to generate a subset of antigens that the immune system recognizes as foreign [3]. Genetic, serological, and biochemical evidence suggests that dysregulated PAD4, and potentially PAD2, activities play a role in both the onset and progression of RA [1]. Cl-amidine, a compound that specifically inactivates PAD4, reduces disease severity and incidence in the collagen-induced model of arthritis (CIA) (unpublished observations). However, because Cl-amidine inhibits all of the PAD isozymes with equipotency, it is unclear whether the observed reduction in disease severity is due to the inhibition of single or multiple PADs. This is particularly relevant because both PAD 2 and 4 are overexpressed in the joints of patients with RA [4]. Thus, the identification of PAD selective inhibitors would facilitate the characterization of their individual contributions to the onset and progression of RA and represent a promising novel therapeutic approach for RA.

Summary of Probe Development Effort:

This probe development effort is focused on the identification of PAD4 inhibitors. All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.

References:

1. Vossenaar, E.R., et al., PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays, 2003. 25(11): p. 1106-18.
2. Smolen, J.S. and G. Steiner, Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov, 2003. 2(6): p. 473-88.
3. Vossenaar, E.R., et al., Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Ann Rheum Dis, 2004. 63(4): p. 373-81.
4. Lundberg, K., et al., Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity. Arthritis Res Ther, 2005. 7(3): p. R458-67.

Keywords:

Summary, Summary AID, protein arginine deiminase, PAD, PAD4, rheumatoid arthritis, RA, collagen-induced model of arthritis, CIA, fluorescence polarization, rhodamine-conjugated F-amidine, RFA, primary screen, HTS, high throughput screen, 384, NIH Validation Collection, Scripps, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN
Additional Information
Grant Number: R01 GM079357-01

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