Issue 26, 2017

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

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

Supplementary files

Article information

Article type
Communication
Submitted
24 Jan 2017
Accepted
16 Feb 2017
First published
07 Mar 2017

Chem. Commun., 2017,53, 3637-3640

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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