Design, Synthesis and SAR Exploration of Tri-substituted 1,2,4-Triazoles as Inhibitors of the Annexin A2-S100A10 Protein Interaction

Tummala Rama Krishna Reddy; Chan  Li; Xiaoxia  Guo; Peter Fischer; Lodewijk  Dekker

doi:10.1016/j.bmc.2014.07.043

Design, Synthesis and SAR Exploration of Tri-substituted 1,2,4-Triazoles as Inhibitors of the Annexin A2-S100A10 Protein Interaction

Tummala Rama Krishna Reddy
, Chan Li
, Xiaoxia Guo
, Peter Fischer
, Lodewijk Dekker

Research output: Contribution to journal › Article › peer-review

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Abstract

Recent target validation studies have shown that inhibition of the protein interaction between annexin A2 and the S100A10 protein may have potential therapeutic benefits in cancer. Virtual screening identified certain 3,4,5-trisubstituted 4H-1,2,4-triazoles as moderately potent inhibitors of this interaction. A series of analogues were synthesized based on the 1,2,4-triazole scaffold and were evaluated for inhibition of the annexin A2–S100A10 protein interaction in competitive binding assays. 2-[(5-{[(4,6-Dimethylpyrimidin-2-yl)sulfanyl]methyl}-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)sulfanyl]-N-[4-(propan-2-yl)phenyl]acetamide (36) showed improved potency and was shown to disrupt the native complex between annexin A2 and S100A10

Original language	English
Pages (from-to)	5378-5391
Journal	Bioorganic and Medicinal Chemistry
Volume	22
Issue number	19
DOIs	https://doi.org/10.1016/j.bmc.2014.07.043
Publication status	Published - 1 Oct 2014

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10.1016/j.bmc.2014.07.043

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Copyright 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).
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title = "Design, Synthesis and SAR Exploration of Tri-substituted 1,2,4-Triazoles as Inhibitors of the Annexin A2-S100A10 Protein Interaction",

abstract = "Recent target validation studies have shown that inhibition of the protein interaction between annexin A2 and the S100A10 protein may have potential therapeutic benefits in cancer. Virtual screening identified certain 3,4,5-trisubstituted 4H-1,2,4-triazoles as moderately potent inhibitors of this interaction. A series of analogues were synthesized based on the 1,2,4-triazole scaffold and were evaluated for inhibition of the annexin A2{\textendash}S100A10 protein interaction in competitive binding assays. 2-[(5-\{[(4,6-Dimethylpyrimidin-2-yl)sulfanyl]methyl\}-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)sulfanyl]-N-[4-(propan-2-yl)phenyl]acetamide (36) showed improved potency and was shown to disrupt the native complex between annexin A2 and S100A10",

author = "Reddy, \{Tummala Rama Krishna\} and Chan Li and Xiaoxia Guo and Peter Fischer and Lodewijk Dekker",

note = "The work described here was supported by Cancer Research UK (Grant reference C21559/A11597 and C21559/A7252). Copyright 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).",

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doi = "10.1016/j.bmc.2014.07.043",

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T1 - Design, Synthesis and SAR Exploration of Tri-substituted 1,2,4-Triazoles as Inhibitors of the Annexin A2-S100A10 Protein Interaction

AU - Reddy, Tummala Rama Krishna

AU - Li, Chan

AU - Guo, Xiaoxia

AU - Fischer, Peter

AU - Dekker, Lodewijk

N1 - The work described here was supported by Cancer Research UK (Grant reference C21559/A11597 and C21559/A7252). Copyright 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

PY - 2014/10/1

Y1 - 2014/10/1

N2 - Recent target validation studies have shown that inhibition of the protein interaction between annexin A2 and the S100A10 protein may have potential therapeutic benefits in cancer. Virtual screening identified certain 3,4,5-trisubstituted 4H-1,2,4-triazoles as moderately potent inhibitors of this interaction. A series of analogues were synthesized based on the 1,2,4-triazole scaffold and were evaluated for inhibition of the annexin A2–S100A10 protein interaction in competitive binding assays. 2-[(5-{[(4,6-Dimethylpyrimidin-2-yl)sulfanyl]methyl}-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)sulfanyl]-N-[4-(propan-2-yl)phenyl]acetamide (36) showed improved potency and was shown to disrupt the native complex between annexin A2 and S100A10

AB - Recent target validation studies have shown that inhibition of the protein interaction between annexin A2 and the S100A10 protein may have potential therapeutic benefits in cancer. Virtual screening identified certain 3,4,5-trisubstituted 4H-1,2,4-triazoles as moderately potent inhibitors of this interaction. A series of analogues were synthesized based on the 1,2,4-triazole scaffold and were evaluated for inhibition of the annexin A2–S100A10 protein interaction in competitive binding assays. 2-[(5-{[(4,6-Dimethylpyrimidin-2-yl)sulfanyl]methyl}-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)sulfanyl]-N-[4-(propan-2-yl)phenyl]acetamide (36) showed improved potency and was shown to disrupt the native complex between annexin A2 and S100A10

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DO - 10.1016/j.bmc.2014.07.043

M3 - Article

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JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 19

ER -

Design, Synthesis and SAR Exploration of Tri-substituted 1,2,4-Triazoles as Inhibitors of the Annexin A2-S100A10 Protein Interaction

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