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Ding Y, O'Keefe H, DeLorey JL, et al. Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT). ACS Med Chem Lett. 2015;6(8):888-93doi: 10.1021/acsmedchemlett.5b00138.
Ding, Y., O'Keefe, H., DeLorey, J. L., Israel, D. I., Messer, J. A., Chiu, C. H., Skinner, S. R., Matico, R. E., Murray-Thompson, M. F., Li, F., Clark, M. A., Cuozzo, J. W., Arico-Muendel, C., & Morgan, B. A. (2015). Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT). ACS medicinal chemistry letters, 6(8), 888-93. https://doi.org/10.1021/acsmedchemlett.5b00138
Ding, Yun, et al. "Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT)." ACS medicinal chemistry letters vol. 6,8 (2015): 888-93. doi: https://doi.org/10.1021/acsmedchemlett.5b00138
Ding Y, O'Keefe H, DeLorey JL, Israel DI, Messer JA, Chiu CH, Skinner SR, Matico RE, Murray-Thompson MF, Li F, Clark MA, Cuozzo JW, Arico-Muendel C, Morgan BA. Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT). ACS Med Chem Lett. 2015 Jul 07;6(8):888-93. doi: 10.1021/acsmedchemlett.5b00138. eCollection 2015 Aug 13. PMID: 26288689; PMCID: PMC4538441.
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ACS Med Chem Lett. 2015 Jul 07;6(8):888-93. doi: 10.1021/acsmedchemlett.5b00138. eCollection 2015 Aug 13.

Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT).

ACS medicinal chemistry letters

Yun Ding, Heather O'Keefe, Jennifer L DeLorey, David I Israel, Jeffrey A Messer, Cynthia H Chiu, Steven R Skinner, Rosalie E Matico, Monique F Murray-Thompson, Fan Li, Matthew A Clark, John W Cuozzo, Christopher Arico-Muendel, Barry A Morgan

Affiliations

  1. Platform Technology & Science, GlaxoSmithKline , ELT-Boston, 830 Winter Street, Waltham, Massachusetts 02451, United States.
  2. Tedor Pharma, Inc. , 400 Highland Corporate Drive, Cumberland, Rhode Island 02864, United States.
  3. Biological Reagent and Assay Development, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
  4. Tufts Healthcare Institute , 136 Harrison Avenue, Boston, Massachusetts 02111, United States.
  5. X-Chem, Inc. , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  6. Center for Drug Discovery, Baylor College of Medicine , One Baylor Plaza, Houston, Texas 77030, United States.

PMID: 26288689 PMCID: PMC4538441 DOI: 10.1021/acsmedchemlett.5b00138

Abstract

The aggrecan degrading metalloprotease ADAMTS-4 has been identified as a novel therapeutic target for osteoarthritis. Here, we use DNA-encoded Library Technology (ELT) to identify novel ADAMTS-4 inhibitors from a DNA-encoded triazine library by affinity selection. Structure-activity relationship studies based on the selection information led to the identification of potent and highly selective inhibitors. For example, 4-(((4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(((4-methylpiperazin-1-yl)methyl)amino)-1,3,5-triazin-2-yl)amino)methyl)-N-ethyl-N-(m-tolyl)benzamide has IC50 of 10 nM against ADAMTS-4, with >1000-fold selectivity over ADAMT-5, MMP-13, TACE, and ADAMTS-13. These inhibitors have no obvious zinc ligand functionality.

Keywords: ADAMTS-4; DNA-encoded library; inhibitors

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