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BioAssay: AID 743013

Summary of the probe development effort to identify exosite inhibitors of ADAM17.

Approximately 20-30% of breast cancer patients have tumors that over-express human epidermal growth factor receptor (HER2), which confers an aggressive tumor phenotype and poor prognosis [1-3]. A Disintegrin and Metalloprotease (ADAM) proteases are responsible for amplification of HER2 signaling due to either cleavage of its extracellular domain or release of HER2 ligands, which leads to more ..
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 Related BioAssays
AID: 743013
Data Source: The Scripps Research Institute Molecular Screening Center (ADAM17_INH_SUMMARY)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2013-11-07
Target
Depositor Specified Assays
AIDNameTypeComment
720648QFRET-based biochemical primary high throughput screening assay to identify exosite inhibitors of ADAM17.screeningPrimary Assay (ADAM17_INH in singlicate)
743256Counterscreen for exosite inhibitors of ADAM17: Fluorescence resonance energy transfer (FRET)-based biochemical high throughput screening assay to identify inhibitors of ADAM10screening
743257QFRET-based biochemical high throughput confirmation assay to identify exosite inhibitors of ADAM17screening
743259Counterscreen for exosite inhibitors of ADAM17: Fluorescence resonance energy transfer (FRET)-based biochemical high throughput dose response assay to identify inhibitors of ADAM10confirmatory
743260QFRET-based biochemical high throughput dose response assay to identify exosite inhibitors of ADAM17confirmatory
743337On Hold
Description:
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Center Affiliation: Torrey Pines Institute for Molecular Sciences (TPIMS)
Assay Provider: Dmitriy Minond, Torrey Pines Institute for Molecular Sciences (TPIMS)
Network: Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R03 DA033985-01
Grant Proposal PI: Dmitriy Minond, Torrey Pines Institute for Molecular Sciences (TPIMS)
External Assay ID: ADAM17_INH_SUMMARY

Name: Summary of the probe development effort to identify exosite inhibitors of ADAM17.

Description:

Approximately 20-30% of breast cancer patients have tumors that over-express human epidermal growth factor receptor (HER2), which confers an aggressive tumor phenotype and poor prognosis [1-3]. A Disintegrin and Metalloprotease (ADAM) proteases are responsible for amplification of HER2 signaling due to either cleavage of its extracellular domain or release of HER2 ligands, which leads to proliferation and inhibition of apoptosis [4, 5]. ADAM proteases implicated in amplification of HER2 signaling [6, 7] are ADAM10 [8, 9] and 17 [10, 11]; therefore, inhibition of these proteases represents a viable approach to the abrogation of HER2 signaling in breast cancer. The specific aims of this proposal, therefore, will focus on (1) screening of the MLPCN library for inhibitors that interact with exosites of ADAM10 and 17, and (2) medicinal chemistry optimization of initial leads in order to develop molecular probes of ADAM10 and 17. Our laboratory is uniquely positioned to achieve these goals due to expertise in development of exosite-binding inhibitors and probes, HTS, and biochemistry of proteases. We will also collaborate with experts in the fields of peptide synthesis, HTS, and medicinal chemistry. The successful completion of the Aims of this proposal will lead to a discovery of novel, potent, and selective small molecule probes for ADAM10 and 17[12]. Using these selective molecular probes alone or in combination with other tools, such as siRNA, antibodies, and other small molecule inhibitors, the researchers will be able to study contributions not only of individual members of the ADAM protease family, but also the interplay of ADAM protease-controlled pathways with other pathways implicated in the progression of breast cancer [13-15].

Summary of Probe Development Effort:

This probe development effort is focused on the identification of inhibitors exosite inhibitors of ADAM17. All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.

References:

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22. Roberge, M., M. Peek, D. Kirchhofer, M.S. Dennis, and R.A. Lazarus, Fusion of two distinct peptide exosite inhibitors of Factor VIIa. Biochem J, 2002. 363(Pt 2): p. 387-93.
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28. Baragi, V.M., G. Becher, A.M. Bendele, R. Biesinger, H. Bluhm, J. Boer, H. Deng, R. Dodd, M. Essers, T. Feuerstein, B.M. Gallagher, Jr., C. Gege, M. Hochgurtel, M. Hofmann, A. Jaworski, L. Jin, A. Kiely, B. Korniski, H. Kroth, D. Nix, B. Nolte, D. Piecha, T.S. Powers, F. Richter, M. Schneider, C. Steeneck, I. Sucholeiki, A. Taveras, A. Timmermann, J. Van Veldhuizen, J. Weik, X. Wu, and B. Xia, A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models. Arthritis Rheum, 2009. 60(7): p. 2008-18.
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Keywords:

SUMMARY, Summary AID, singlicate, exosite, ADAM, ADAM17, TACE, protease, enzyme, fluorescence, FRET, binding, cancer, HTS, high throughput screen, 1536, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Additional Information
Grant Number: 1 R03 DA033985-01

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