AMPK Methods and Protocols

Chapter 12

Compound C/Dorsomorphin: Its Use and Misuse as an AMPK

Inhibitor

Biplab Dasgupta and William Seibel

Abstract

The evolutionary conserved energy sensor AMPK plays crucial roles in many biological processes—both
during normal development and pathology. Loss-of-function genetic studies in mice as well as in lower
organisms underscore its importance in embryonic development, stress physiology in the adult, and in key
metabolic disorders including cardiovascular disease, diabetes, cancer, and metabolic syndrome. In contrast
to several other kinases important in human health and medicine where specific/selective inhibitors are
available, no AMPK-specific inhibitors are available. The only reagent called dorsomorphin or compound C
that is occasionally used as an AMPK inhibitor unfortunately inhibits several other kinases much more
potently than AMPK and is therefore highly non-specific. In this chapter, we discuss the pros and cons of
using this reagent to study AMPK functions.

KeywordsAMPK, Compound C, Dorsomorphin, Cancer, Metabolism

1 Introduction

From unicellular organisms to mammals, AMP-activated protein

kinase, or AMPK, functions as an evolutionarily conserved energy

sensor [1, 2]. Reduced ATP production (e.g., nutrient and oxygen

limitation, starvation/caloric restriction) or increased ATP con-

sumption (e.g., exercise, activation of motor proteins, ion channels,

and unchecked cellular biosynthesis) increases the cellular

AMP-ATP ratio and activates AMPK. Active AMPK inhibits

ATP-consuming pathways and augments ATP-producing pathways

to restore energy homeostasis by both transcriptional and post-

translational regulations. AMPK executes numerous cellular func-

tions and is required for adaptive responses to various physiological

and pathological conditions. Studies from AMPK knockout organ-

isms including mice indicate essential as well as redundant functions

of the several isoforms of the AMPK heterotrimeric complex

[3–11]. Work from knockout mouse models also revealed

conflicting results, particularly on AMPK’s response to drugs

Dietbert Neumann and Benoit Viollet (eds.),AMPK: Methods and Protocols, Methods in Molecular Biology, vol. 1732,
https://doi.org/10.1007/978-1-4939-7598-3_12,©Springer Science+Business Media, LLC 2018

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