DRUG DISCOVERY
Mitosis as a potential therapeutic target for cancer? A divided topic Mitosis plays an essential role in
are disrupted during cancers, leading
growth and cellular replacement,
to uncontrolled proliferation.”
and is often dysregulated in cancers, making the process of therapeutic interest. Researchers
The lab’s aim is to follow this complex signaling cascade at the molecular level, which requires the development
at the University of North
of novel fluorescence microscopy tools
Carolina at Chapel Hill (UNC
for high content screening. Fortunately,
Chapel Hill) are developing
the group was able to draw on
novel cell imaging tools to help them classify key components of mitosis and identify new therapeutic targets.
expertise from within the department, as Klaus Hahn, Thurman Distinguished Professor of Pharmacology, explained:
Nicholas Brown, Assistant Professor in Pharmacology
“My lab focuses on building molecules that are used for a wide range of
groups abutting each other?’ or ‘what
imaging applications in biosensors,
do they sit on?’. This simply isn’t
optogenetics and chemogenetics. We
something you normally do in live cell
Mitosis is the stage of the cell cycle
use them ourselves to study immune
imaging – it is tough to go into that
where replicated chromosomes divide
cells and motility, but my lab is
kind of detail in a live cell. But as a
into two new nuclei, giving rise to
probably best known for the
chemist, these are very interesting
genetically identical cells. In healthy
application of these tools in other labs.
questions to study.”
systems, this process only occurs when
Nick therefore approached me with
we are growing, or need to replace old
what sounded like a really fun and
The joint UNC Chapel Hill team has
or damaged cells. However, cells grow
exciting application of these molecules.
developed a unique fluorescence-
and divide uncontrollably in cancers.
He had this exquisitely detailed cellular
based ‘binder/tag’ approach capable of
Therefore, fully understanding which
system, and wanted to ask molecule
reporting the conformational changes
molecules control mitosis, as well as
level questions, such as ‘which
of individual molecules in live cells
what stage of the process they affect,
conformational changes are
(Figure 1). The advantage of this system
is of interest for the identification of
occurring?’, ‘how are the different
is that only a very short, seven-peptide tag is inserted into the protein of
new therapeutic targets. Nicholas
interest, minimizing the risk of
Brown, Assistant Professor in
disruption to normal protein or cellular
Pharmacology at the UNC Chapel Hill
function. The team is now developing
School of Medicine, explained: “The
and optimizing cell lines with a range of
process of mitosis is controlled by a
tagged proteins for high content
signaling cascade called the spindle assembly checkpoint, at the heart of which is the anaphase-promoting complex (APC). The APC functions as a ubiquitin ligase, adding ubiquitin chains
= binder
screening. Klaus commented:
= tag
biosensor molecules in live cells for
and rounds of cell growth under
proteasome degradation and move the
different conditions. While this is the
cell cycle forward. During normal cell
bread and butter of biosensor
function, the spindle assembly
development, it is normally quite time
checkpoint uses a variety of ‘silencing
consuming. Fortunately, just before
factors’ to inhibit the activity of the cell cycle – but these inhibitory signals 14
TECAN JOURNAL 1/2022
imaging applications is a very tedious process. This means multiple iterations
to macromolecules to target them for
APC – preventing progression of the
“Traditionally, optimizing expression of
Figure 1: Schematic of the binder/tag approach1
starting this project, we were approached by Tecan with the offer to
