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Related Experiment Video

Updated: Apr 11, 2026

Identification of Kinase-substrate Pairs Using High Throughput Screening

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Published on: August 29, 2015

Covalent Reprogramming of Kinase Binders to Modulate Protein Abundance.

Chen Mozes¹, Xiaokang Jin¹, Miguel A Campos¹

¹Department of Chemistry, Northwestern University, Evanston, USA.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)

|April 9, 2026

Summary

New covalent small molecules can reprogram protein abundance. One compound, MKI-AA, stabilizes Aurora kinase A (AURKA) by preventing its degradation, while structural changes can reverse this effect.

Keywords:

enzymes kinases protein degraders protein stabilizers proteomics

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Area of Science:

Chemical Biology
Molecular Pharmacology
Proteomics

Background:

Small molecules modulating protein abundance offer alternatives to traditional inhibition.
Targeting protein degradation pathways is a growing area in drug discovery.

Purpose of the Study:

To explore how covalent modifications to a multi-kinase inhibitor scaffold affect protein abundance.
To investigate the mechanism by which MKI-AA stabilizes Aurora kinase A (AURKA).

Main Methods:

Synthesis of multi-kinase inhibitor analogs with electrophilic groups.
Quantitative proteomics to assess global protein abundance changes.
Biochemical assays to determine the mechanism of AURKA stabilization.

Main Results:

MKI-AA, a multi-kinase inhibitor with an acrylamide warhead, uniquely stabilizes AURKA.
MKI-AA acts post-translationally, inhibiting AURKA ubiquitination and proteasomal degradation.
Proteomic analysis revealed altered AURKA interactions upon MKI-AA treatment.
Structural modifications inverted MKI-AA's function from stabilization to degradation.

Conclusions:

Covalent small molecules can be designed to specifically modulate protein stability.
AURKA stabilization by MKI-AA offers a new therapeutic strategy.
Subtle structural changes can drastically alter the functional outcome of small molecules.