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Issue 26, 2017
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Discovery of a new class of highly potent necroptosis inhibitors targeting the mixed lineage kinase domain-like protein

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Abstract

We report the development of novel Mixed Lineage Kinase Domain-Like protein (MLKL) inhibitors with single nanomolar potency (compound 15 is also named as TC13172). Using the converting biochemistry to chemistry activity-based protein profiling (BTC-ABPP) method, we were able to determine that the inhibitors covalently bind to Cysteine86 (Cys-86) of MLKL. This is the first example of the use of LC-MS/MS to identify the binding site of an MLKL inhibitor. The novel MLKL inhibitors provide powerful tools to study the biological function of MLKL and demonstrate that MLKL should be viewed as a druggable target.

Graphical abstract: Discovery of a new class of highly potent necroptosis inhibitors targeting the mixed lineage kinase domain-like protein

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Publication details

The article was received on 24 Jan 2017, accepted on 16 Feb 2017 and first published on 07 Mar 2017


Article type: Communication
DOI: 10.1039/C7CC00667E
Citation: Chem. Commun., 2017,53, 3637-3640
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    Discovery of a new class of highly potent necroptosis inhibitors targeting the mixed lineage kinase domain-like protein

    B. Yan, L. Liu, S. Huang, Y. Ren, H. Wang, Z. Yao, L. Li, S. Chen, X. Wang and Z. Zhang, Chem. Commun., 2017, 53, 3637
    DOI: 10.1039/C7CC00667E

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